Fused imidazopyridines as reversible inhibitors of brutons tyrosine kinase (btk)

ABSTRACT

The present invention relates to fused imidazo pyridine compounds, and pharmaceutically acceptable compositions thereof, useful as BTK inhibitors.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to fused imidazo pyridine compounds thatare useful as inhibitors of Bruton's Tyrosine Kinase (BTK). Theinvention also provides pharmaceutically acceptable compositionscomprising compounds of the present invention and methods of using saidcompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Protein kinases constitute one of the largest families of human enzymesand regulate many different signaling processes by adding phosphategroups to proteins (T. Hunter, Cell 1987 50:823-829). Specifically,tyrosine kinases phosphorylate proteins on the phenolic moiety oftyrosine residues. The tyrosine kinase family includes members thatcontrol cell growth, migration, and differentiation. Abnormal kinaseactivity has been implicated in a variety of human diseases includingcancers, autoimmune and inflammatory diseases. Since protein kinases areamong the key regulators of cell signaling, they provide a target tomodulate cellular function with small molecular kinase inhibitors andthus make good drug targets. In addition to treatment of kinase-mediateddisease processes, selective and efficacious inhibitors of kinaseactivity are also useful for investigation of cell signaling processesand identification of other cellular targets of therapeutic interest.

There is good evidence that B-cells play a key role in the pathogenesisof autoimmune and/or inflammatory disease. Protein-based therapeuticsthat deplete B cells such as Rituxan are effective againstautoantibody-driven inflammatory diseases such as rheumatoid arthritis(Rastetter et al. Annu Rev Med 2004 55:477). Therefore inhibitors of theprotein kinases that play a role in B-cell activation should be usefultherapeutics for B-cell mediated disease pathology, such as autoantibodyproduction.

Signaling through the B-cell receptor (BCR) controls a range of B-cellresponses including proliferation and differentiation into matureantibody producing cells. The BCR is a key regulatory point for B-cellactivity and aberrant signaling can cause deregulated B-cellproliferation and formation of pathogenic autoantibodies that lead tomultiple autoimmune and/or inflammatory diseases. Bruton's TyrosineKinase (BTK) is a non-BCR associated kinase that is membrane proximaland immediately downstream from BCR. Lack of BTK has been shown to blockBCR signaling and therefore inhibition of BTK could be a usefultherapeutic approach to block B-cell mediated disease processes. Also,BTK has been reported to play a role in apoptosis (Islam and SmithImmunol. Rev. 2000 178:49,) and thus BTK inhibitors would be useful forthe treatment of certain B-cell lymphomas and leukemias (Feldhahn et al.J. Exp. Med. 2005 201:1837).

BTK is a member of the Tec family of tyrosine kinases, and has beenshown to be a critical regulator of early B-cell development and matureB-cell activation and survival (Khan et al. Immunity 1995 3:283;Ellmeier et al. J. Exp. Med. 2000 192:1611). Mutation of BTK in humansleads to the condition X-linked agammaglobulinemia (XLA) (reviewed inRosen et al. New Eng. J. Med. 1995 333:431 and Lindvall et al. Immunol.Rev. 2005 203:200). These patients are immune-compromised and showimpaired maturation of B-cells, decreased immunoglobulin and peripheralB-cell levels, diminished T-cell independent immune responses as well asattenuated calcium mobilization following BCR stimulation.

Evidence for a role for BTK in autoimmune and inflammatory diseases hasalso been provided by BTK-deficient mouse models. In preclinical murinemodels of systemic lupus erythematosus (SLE), BTK-deficient mice showmarked amelioration of disease progression. In addition, BTK-deficientmice are resistant to collagen-induced arthritis (Jansson and HolmdahlClin. Exp. Immunol. 1993 94:459). A selective BTK inhibitor hasdemonstrated dose-dependent efficacy in a mouse arthritis model (Z. Panet al., Chem. Med Chem. 2007 2:58-61).

BTK is also expressed by cells other than B-cells that may be involvedin disease processes. BTK is key component of Fc-gamma signaling inmyeloid cells. For example, BTK is expressed by mast cells andBTK-deficient bone marrow derived mast cells demonstrate impairedantigen induced degranulation (Iwaki et al. J. Biol. Chem. 2005280:40261). This shows BTK could be useful to treat pathological mastcells responses such as allergy and asthma. Also monocytes from XLApatients, in which BTK activity is absent, show decreased TNF alphaproduction following stimulation (Horwood et al. J Exp Med 197:1603,2003). Therefore TNF alpha mediated inflammation could be modulated bysmall molecular BTK inhibitors.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of BTK. Such compounds have general formula I:

or a tautomer, or a pharmaceutically acceptable salt, hydrate, solvate,or prodrug thereof, wherein each of X, Y, ring Z, R¹, R^(a), n, and p,is as defined and described in embodiments herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with BTK. Such diseases, disorders,or conditions include those described herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In certain aspects, the present invention provides for inhibitors ofBTK. In some embodiments, such compounds include those of the formulaedescribed herein, or a pharmaceutically acceptable salt thereof, whereineach variable is as defined and described herein.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York. 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Exemplary aliphatic groups are linear or branched, substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus (including, any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. The term “aryl”is used interchangeably with the term “aryl ring”. In certainembodiments of the present invention, “aryl” refers to an aromatic ringsystem. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyland the like, which optionally includes one or more substituents. Alsoincluded within the scope of the term “aryl”, as it is used herein, is agroup in which an aromatic ring is fused to one or more non-aromaticrings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group is optionally mono- or bicyclic. The term “heteroaryl”is used interchangeably with the terms “heteroaryl ring”, “heteroarylgroup”, or “heteroaromatic”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl),or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclicgroup”, “heterocyclic moiety”, and “heterocyclic radical”, are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group is optionally mono- or bicyclic.The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, certain compounds of the invention contain“optionally substituted” moieties. In general, the term “substituted”,whether preceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. “Substituted” applies to one or more hydrogens that areeither explicit or implicit from the structure (e.g.,

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group has asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure is substituted withmore than one substituent selected from a specified group, thesubstituent is either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable”, as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently deuterium; halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which are optionallysubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which is optionallysubstituted with R^(∘); —CH═CHPh, which is optionally substituted withR^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which is optionally substituted withR^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘), SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂₀R^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) is optionally substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which is optionally substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently deuterium, halogen, —(CH₂)₀₋₂R^(●),-(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂;—O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH,—(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂,—(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃,—C(O)SR^(●), —(C₁₋₄ straight or branched alkylene)C(O)OR^(●), or—SSR^(●) wherein each R^(●) is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(∘) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which is substituted as defined below, oran unsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which is optionally substitutedas defined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which is optionallysubstituted as defined below, unsubstituted —OPh, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R,taken together with their intervening atom(s) form an unsubstituted3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain embodiments, the terms “optionally substituted”, “optionallysubstituted alkyl,” “optionally substituted “optionally substitutedalkenyl,” “optionally substituted alkynyl”, “optionally substitutedcarbocyclic,” “optionally substituted aryl”, “optionally substitutedheteroaryl,” “optionally substituted heterocyclic,” and any otheroptionally substituted group as used herein, refer to groups that aresubstituted or unsubstituted by independent replacement of one, two, orthree or more of the hydrogen atoms thereon with typical substituentsincluding, but not limited to:

—F, —Cl, —Br, —I, deuterium,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NHcycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino,-diarylamino, -diheteroarylamino,

—O— alkyl, —O— alkenyl, —O— alkynyl, —O— cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocyclic,

—C(O)— alkyl, —C(O)— alkenyl, —C(O)— alkynyl, —C(O)— carbocyclyl,—C(O)-aryl, —C(O)— heteroaryl, —C(O)-heterocyclyl,

—CONH₂, —CONH— alkyl, —CONH— alkenyl, —CONH— alkynyl, —CONH-carbocyclyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocyclyl,

—OCO₂— alkyl, —OCO₂— alkenyl, —OCO₂— alkynyl, —OCO₂— carbocyclyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocyclyl, —OCONH₂, —OCONH—alkyl, —OCONH— alkenyl, —OCONH— alkynyl, —OCONH— carbocyclyl, —OCONH—aryl, —OCONH— heteroaryl, —OCONH— heterocyclyl,

—NHC(O)— alkyl, —NHC(O)— alkenyl, —NHC(O)— alkynyl, —NHC(O)—carbocyclyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclyl,—NHCO₂— alkyl, —NHCO₂— alkenyl, —NHCO₂— alkynyl, —NHCO₂— carbocyclyl,—NHCO₂— aryl, —NHCO₂— heteroaryl, —NHCO₂-heterocyclyl, —NHC(O)NH₂,—NHC(O)NH— alkyl, —NHC(O)NH— alkenyl, —NHC(O)NH— alkenyl, —NHC(O)NH—carbocyclyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH—heterocyclyl, NHC(S)NH₂, —NHC(S)NH— alkyl, —NHC(S)NH— alkenyl,—NHC(S)NH— alkynyl, —NHC(S)NH— carbocyclyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocyclyl, —NHC(NH)NH₂, —NHC(NH)NH—alkyl, —NHC(NH)NH— -alkenyl, —NHC(NH)NH— alkenyl, —NHC(NH)NH—carbocyclyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH—heterocyclyl, —NHC(NH)— alkyl, —NHC(NH)— alkenyl, —NHC(NH)— alkenyl,—NHC(NH)— carbocyclyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocyclyl,

—C(NH)NH— alkyl, —C(NH)NH— alkenyl, —C(NH)NH— alkynyl, —C(NH)NH—carbocyclyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocyclyl,

—S(O)— alkyl, —S(O)— alkenyl, —S(O)— alkynyl, —S(O)— carbocyclyl,—S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocyclyl —SO₂NH₂, —SO₂NH— alkyl,—SO₂NH— alkenyl, —SO₂NH— alkynyl, —SO₂NH— carbocyclyl, —SO₂NH— aryl,—SO₂NH— heteroaryl, —SO₂NH— heterocyclyl,

—NHSO₂— alkyl, —NHSO₂— alkenyl, —NHSO₂— alkynyl, —NHSO₂— carbocyclyl,—NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocyclyl,

—CH₂NH₂, —CH₂SO₂CH₃,

-mono-, di-, or tri-alkyl silyl,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic,-heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy,-methoxyethoxy, —SH, —S— alkyl, —S— alkenyl, —S— alkynyl, —S—carbocyclyl, —S-aryl, —S-heteroaryl, —S-heterocyclyl, ormethylthiomethyl.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.

As used herein, the term “tautomer” means each of two or more isomers ofa compound that exist together in equilibrium, and are readilyinterchanged by migration of an atom or group within the molecule.Tautomers are constitutional isomers of organic compounds that readilyinterconvert by a chemical reaction called tautomerization. Thisreaction commonly results in the formal migration of a hydrogen atom orproton, accompanied by a switch of a single bond and adjacent doublebond. For example, see

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. In some embodiments, the groupcomprises one or more deuterium atoms.

There is furthermore intended that a compound of the formula I includesisotope-labeled forms thereof. An isotope-labeled form of a compound ofthe formula I is identical to this compound apart from the fact that oneor more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phos-phorus,fluo-rine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²p ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I, aprodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otherisotopes of other atoms is intended to be part of the present invention.An isotope-labeled compound of the formula I can be used in a number ofbeneficial ways. For example, an isotope-labeled compound of the formulaI into which, for example, a radioisotope, such as ³H or ¹⁴C, has beenincorporated, is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labeled compound. Higher metabolic stability translates directlyinto an increased in vivo half-life or lower dosages, which under mostcircumstances would represent a preferred embodiment of the presentinvention. An isotope-labeled compound of the formula I can usually beprepared by carrying out the procedures disclosed in the synthesisschemes and the related description, in the example part and in thepreparation part in the present text, replacing a non-isotope-labeledreactant by a readily available isotope-labeled reactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus causes a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a com-poundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art is able to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favorable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favorable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

As used herein, the term “modulator” is defined as a compound that bindsto and/or inhibits the target with measurable affinity. In certainembodiments, a modulator has an IC₅₀ and/or binding constant of lessabout 50 μM, less than about 5 μM, less than about 1 μM, less than about500 nM, less than about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in BTK activity between a samplecomprising a compound of the present invention, or composition thereof,and BTK, and an equivalent sample comprising BTK, in the absence of saidcompound, or composition thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

3. Description of Exemplary Compounds

According to one aspect, the present invention provides a compound offormula I,

or a tautomer, or a pharmaceutically acceptable salt, hydrate, solvate,or prodrug thereof,wherein:

-   X is C(R)₂ or O;-   Y is —O—, —S—, —SO₂—, —SO—, —C(O)—, —CO₂—, —C(O)N(R²)—, —NR²C(O)—,    —NR²C(O)N(R)—, —NR²SO₂—, or —N(R²)—;-   R¹ is C₅₋₁₀ aryl, a 3-8 membered saturated or partially unsaturated    carbocyclic ring, 3-7 membered heterocylic ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur; each of which is optionally substituted;-   Ring Z is C₅₋₁₀ aryl, a 3-8 membered saturated or partially    unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur; each of which is optionally substituted;-   each R^(a) is independently —R, halogen, —OR, —SR, —CN, —NO₂, —SO₂R,    —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂; or two R^(a) groups, together with the atoms to which each    is attached, forms a C₅₋₁₀ aryl, a 3-8 membered saturated or    partially unsaturated carbocyclic ring, a 3-7 membered heterocylic    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur; each of which is optionally substituted;-   each R is independently hydrogen, C₁₋₆ aliphatic, C₅₋₁₀ aryl, a 3-8    membered saturated or partially unsaturated carbocyclic ring, a 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; each of which is    optionally substituted; or-   two R groups on the same atom are taken together with the atom to    which they are attached to form a C₅₋₁₀ aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur; a 10-15 membered fused aryl ring; a 6-15    membered saturated or partially unsaturated fused carbocyclic ring;    a 10-15 membered fused heteroaryl ring; or a 6-15 membered saturated    or partially unsaturated fused heterocyclic ring; each of which is    optionally substituted;-   n is 0, 1, or 2; and-   p is 0, 1, 2, or 3.

In certain embodiments, X is CH₂. In certain embodiments, X is O.

In certain embodiments, X is CH₂ and n is 1.

In certain embodiments, X is CH₂ and n is 2.

In certain embodiments, X is O and n is 1.

In certain embodiments, X is O and n is 2.

In certain embodiments, Y is —C(O)—, —CO₂—, —C(O)N(R²)—, —NR²C(O)—,—NR²C(O)N(R)—, —NR²SO₂—, or —N(R²)—.

In certain embodiments, Y is —C(O)N(R²)—, —NR²C(O)—, —NR²C(O)N(R)—, or—NR²SO₂.

In certain embodiments, Y is —NR²C(O)—.

In certain embodiments, Y is —C(O)N(R²)—.

In certain embodiments, R¹ is an optionally substituted 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; or R¹ is an optionally substituted 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In certain embodiments, R¹ is an optionally substituted 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.

In certain embodiments, R¹ is an optionally substituted 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

In certain embodiments, R¹ is azocinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro [2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,piperazinyl, piperidinyl, piperidine-one, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,tetrahydrofuranyl, tetrahydropyridine, tetrahydropyran,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thiazolyl, thienyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,oxetanyl, or azetidinyl; each of which is optionally substituted.

In certain embodiments, R¹ is imidazolidinyl, imidazolinyl, imidazolyl,isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,oxazolidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2H-pyrrolyl, pyrrolyl, oxetanyl, or azetidinyl; each of which isoptionally substituted.

In certain embodiments, R¹ is selected from:

In certain embodiments, Ring Z is a 3-8 membered saturated or partiallyunsaturated carbocyclic ring or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each of which is optionally substituted.

In certain embodiments, Ring Z is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, or isothiazolyl; each of which isoptionally substituted.

In certain embodiments, Ring Z is cyclopropyl, imidazolyl, pyrazolyl, orpyridyl; each of which is optionally substituted.

In certain embodiments, Ring Z is

In certain embodiments, Ring Z is

In certain embodiments, each of X, Y, Ring Z, R¹, R^(a), n, and p, is asdefined above and described in embodiments, classes and subclasses aboveand herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula II,

or a pharmaceutically acceptable salt thereof, wherein each of Ring Z,R¹, R^(a), and p, is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula III,

or a pharmaceutically acceptable salt thereof, wherein each of Ring Z,R¹, R^(a), and p, is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula IV,

or a pharmaceutically acceptable salt thereof, wherein each of Ring Z,R¹, R^(a), and p, is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound selected fromTable 1:

1

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190

In some embodiments, the present invention provides a compound selectedfrom those depicted above, or a pharmaceutically acceptable saltthereof.

Various structural depictions may show a heteroatom without an attachedgroup, radical, charge, or counterion. Those of ordinary skill in theart are aware that such depictions are meant to indicate that theheteroatom is attached to hydrogen (e.g.,

is understood to be

In certain embodiments, the compounds of the invention were synthesizedin accordance with the schemes provided in the Examples below.

4. Uses, Formulation and Administration Pharmaceutically AcceptableCompositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit BTK, or a mutant thereof,in a biological sample or in a patient. In certain embodiments, theamount of compound in compositions of this invention is such that iseffective to measurably inhibit BTK, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition.

The term “patient” or “subject”, as used herein, means an animal,preferably a mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat are used in the compositions of this invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

Compositions of the present invention are administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention include aqueous or oleaginous suspension.These suspensions are formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that are employed are water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium.

For this purpose, any bland fixed oil employed includes synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents that arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms arealso be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention are orallyadministered in any orally acceptable dosage form. Exemplary oral dosageforms are capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents are optionally also added.

Alternatively, pharmaceutically acceptable compositions of thisinvention are administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention are alsoadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches are also used.

For topical applications, provided pharmaceutically acceptablecompositions are formulated in a suitable ointment containing the activecomponent suspended or dissolved in one or more carriers. Exemplarycarriers for topical administration of compounds of this aremineral oil,liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene,polyoxypropylene compound, emulsifying wax and water. Alternatively,provided pharmaceutically acceptable compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

Pharmaceutically acceptable compositions of this invention areoptionally administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and are prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that are optionallycombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, provided compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe compound can be administered to a patient receiving thesecompositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In certain embodiments, the invention provides a method for inhibitingBTK, or a mutant thereof, in a patient or in a biological samplecomprising the step of administering to said patient or contacting saidbiological sample with a compound according to the invention.

In certain embodiments, the invention is directed to the use ofcompounds of the invention and/or physiologically acceptable saltsthereof, for modulating or inhibiting a BTK enzyme. The term“modulation” denotes any change in BTK-mediated signal transduction,which is based on the action of the specific inventive compounds capableto interact with the BTK target in such a manner that makes recognition,binding and activating possible. The compounds are characterized by sucha high affinity to BTK, which ensures a reliable binding of BTK. Incertain embodiments, the substances are highly selective for BTK overmost other kinases in order to guarantee an exclusive and directedrecognition with the single BTK target. In the context of the presentinvention, the term “recognition”—without being limited thereto—relatesto any type of interaction between the specific compounds and thetarget, particularly covalent or non-covalent binding or association,such as a covalent bond, hydrophobic/hydrophilic interactions, van derWaals forces, ion pairs, hydrogen bonds, ligand-receptor(enzyme-inhibitor) interactions, and the like. Such association may alsoencompass the presence of other molecules such as peptides, proteins ornucleotide sequences. The presentprotein/ligand(enzyme-inhibitor)-interaction is characterized by highaffinity, high selectivity and minimal or even lacking cross-reactivityto other target molecules to exclude unhealthy and harmful impacts tothe treated subject.

In certain embodiments, the present invention relates to a method forinhibiting a BTK enzyme, with at least one compound of formula (I)according to the invention and/or physiologically acceptable saltsthereof, under conditions such that said BTK enzyme is inhibited. Incertain embodiments, the system is a cellular system. In otherembodiments, the system is an in-vitro translation which is based on theprotein synthesis without living cells. The cellular system is definedto be any subject provided that the subject comprises cells. Hence, thecellular system can be selected from the group of single cells, cellcultures, tissues, organs and animals. In certain embodiments, themethod for modulating a BTK enzyme is performed in-vitro. The priorteaching of the present specification concerning the compounds offormula (I), including any embodiments thereof, is valid and applicablewithout restrictions to the compounds according to formula (I) and theirsalts when used in the method for inhibiting BTK. The prior teaching ofthe present specification concerning the compounds of formula (I),including any embodiments thereof, is valid and applicable withoutrestrictions to the compounds according to formula (I) and their saltswhen used in the method for inhibiting BTK.

Patients with mutations in BTK have a profound block in B celldevelopment, resulting in the almost complete absence of mature Blymphocytes and plasma cells, severely reduced Ig levels and a profoundinhibition of humoral response to recall antigens (reviewed in Vihinenet al Frontiers in Bioscience 5: d917-928). Mice deficient in BTK alsohave a reduced number of peripheral B cells and greatly decreased serumlevels of IgM and IgG3. BTK deletion in mice has a profound effect on Bcell proliferation induced by anti-IgM, and inhibits immune responses tothymus-independent type II antigens (Ellmeier et al, J Exp Med 192:1611-1623 (2000)). BTK also plays a crucial role in mast cell activationthrough the high-affinity IgE receptor (Fc epsilon RI). BTK deficientmurine mast cells have reduced degranulation and decreased production ofproinflammatory cytokines following Fc epsilon RI cross-linking(Kawakami et al. Journal of Leukocyte Biology 65: 286-290).

Provided compounds are inhibitors of BTK and are therefore useful fortreating one or more disorders associated with activity of BTK. Thus, insome embodiments, the present invention provides a method for treating aBTK-mediated disorder comprising the step of administering to a patientin need thereof a compound of the present invention, or pharmaceuticallyacceptable composition thereof.

As used herein, the term “BTK-mediated” disorders or conditions as usedherein means any disease or other deleterious condition in which BTK, ora mutant thereof, is known to play a role. Accordingly, anotherembodiment of the present invention relates to treating or lessening theseverity of one or more diseases in which BTK, or a mutant thereof, isknown to play a role. Specifically, the present invention relates to amethod of treating or lessening the severity of a disease or conditionselected from a proliferative disorder or an autoimmune disorder,wherein said method comprises administering to a patient in need thereofa compound or composition according to the present invention.

In some embodiments, the present invention provides a method fortreating or lessening the severity of one or more diseases andconditions associated with BTK. In some embodiments, the disease orcondition is an autoimmune disease, e.g., inflammatory bowel disease,arthritis, systemic lupus erythematosus (SLE or lupus), lupus nephritis,vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoidarthritis (RA), psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis,Sjogren's syndrome, multiple sclerosis (MS), systemic sclerosis, Lymeneuroborreliosis, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylosis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia,celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenicpurpura, optic neuritis, scleroderma, primary biliary cirrhosis,Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,membranous glomerulonephropathy, endometriosis, interstitial cystitis,pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, orvulvodynia. In certain embodiments, the disease or condition is systemiclupus erythematosus (SLE or lupus) or lupus nephritis. In certainembodiments, the disease or condition is RA. In certain embodiments, thedisease or condition is MS.

In some embodiments, the disease or condition is a hyperproliferativedisease or immunologically-mediated diseases including rejection oftransplanted organs or tissues and Acquired Immunodeficiency Syndrome(AIDS, also known as HIV).

In some embodiments, the present invention provides a method fortreating or lessening the severity of one or more diseases andconditions associated with BTK, wherein the disease or condition isselected from heteroimmune conditions or diseases, which include, butare not limited to graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis.

In some embodiments, the present invention provides a method fortreating or lessening the severity of one or more diseases andconditions associated with BTK, wherein the disease or condition isselected from an inflammatory disease, e.g., asthma, appendicitis,atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis,bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronicgraft rejection, colitis, conjunctivitis, Crohn's disease, cystitis,dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis,endometritis, enteritis, enterocolitis, epicondylitis, epididymitis,fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonleinpurpura, hepatitis, hidradenitis suppurativa, immunoglobulin Anephropathy, interstitial lung disease, laryngitis, mastitis,meningitis, myelitis myocarditis, myositis, nephritis, oophoritis,orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis,ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments, the present invention provides a method fortreating or lessening the severity of one or more diseases andconditions associated with BTK, wherein the disease or condition iscancer. In one embodiment, the cancer is a B-cell proliferativedisorder, e.g., diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acutelymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma,multiple myeloma (also known as plasma cell myeloma), non-Hodgkin'slymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone Bcell lymphoma, nodal marginal zone B cell lymphoma, mantle celllymphoma, mediastinal (thymic) large B cell lymphoma, intravascularlarge B cell lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments,the cancer is breast cancer, prostate cancer, or cancer of the mastcells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma,systemic mastocytosis). In one embodiment, the cancer is bone cancer. Inanother embodiment, the cancer is of other primary origin andmetastasizes to the bone. In certain embodiments, the cancer iscolorectal cancer or pancreatic cancer.

In some embodiments, the present invention provides a method fortreating or lessening the severity of one or more diseases or conditionsassociated with BTK including diseases of the bone and joints including,without limitation, rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome,systemic sclerosis, osteoporosis, bone cancer, and bone metastasis.

In some embodiments, the present invention provides a method fortreating or lessening the severity of one or more diseases andconditions associated with BTK, wherein the disease or condition isselected from a thromboembolic disorder or cardiovascular disorder,e.g., myocardial infarct, angina pectoris, reocclusion afterangioplasty, restenosis after angioplasty, reocclusion afteraortocoronary bypass, restenosis after aortocoronary bypass, stroke,transitory ischemia, a peripheral arterial occlusive disorder, pulmonaryembolism, or deep venous thrombosis. In certain embodiments, the presentinvention provides an anti-thrombotic agent because Btk is also involvedin the activation of platelets.

In some embodiments, the present invention provides a method fortreating or lessening the severity of one or more diseases andconditions associated with BTK, including infectious and noninfectiousinflammatory events and autoimmune and other inflammatory diseases.These autoimmune and inflammatory diseases, disorders, and syndromesinclude inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,psoriatic arthritis, juvenile arthritis, osteoarthritis, chronicidiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia,myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis,degenerative joint disease, vitiligo, autoimmune hypopituitarism,Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosisfungoides, acute inflammatory responses (such as acute respiratorydistress syndrome and ischemia/reperfusion injury), and Graves' disease.In certain embodiments, the diabetes is type I diabetes.

In some embodiments, the present invention provides a method fortreating or lessening the severity of one or more diseases andconditions associated with BTK, selected from rheumatoid arthritis,multiple sclerosis, B-cell chronic lymphocytic leukemia, acutelymphocytic leukemia, hairy cell leukemia, non-Hodgkin's lymphoma,Hodgkin's lymphoma, multiple myeloma, bone cancer, bone metastasis,osteoporosis, diabetes (e.g. type I diabetes), irritable bowel syndrome,Crohn's disease, lupus and renal transplant.

It is another object of the invention to provide a method for treatingdiseases that are caused, mediated and/or propagated by BTK activity,wherein at least one compound of formula (I) according to the inventionand/or physiologically acceptable salts thereof is administered to amammal in need of such treatment. In certain embodiments, the inventionprovides a method for treating lupus, wherein at least one compound offormula (I) according to the invention and/or physiologically acceptablesalts thereof is administered to a mammal in need of such treatment. Incertain embodiments, the compound is administered in an effective amountas defined above. In certain embodiments, the treatment is an oraladministration.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to inhibit BTK activity, usuallybetween about one hour and one week. In-vitro treatment can be carriedout using cultivated cells from a biopsy sample or cell line.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing BTK-dependent signal transduction pathways in animals and/orcell culture models or in the clinical diseases mentioned in thisapplication.

Moreover, the subsequent teaching of the present specificationconcerning the use of the compounds according to formula (I) and itsderivatives for the production of a medicament for the prophylactic ortherapeutic treatment and/or monitoring is considered as valid andapplicable without restrictions to the use of the compound for theinhibition of BTK activity if expedient.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by BTK activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byBTK activity. In certain embodiments, the invention provides the use ofa compound according to formula I or physiologically acceptable saltsthereof, for the production of a medicament for the prophylactic ortherapeutic treatment of a BTK-mediated disorder.

Compounds of formula (I) and/or a physiologically acceptable saltthereof can furthermore be employed as intermediate for the preparationof further medicament active ingredients. The medicament is preferablyprepared in a non-chemical manner, e.g. by combining the activeingredient with at least one solid, fluid and/or semi-fluid carrier orexcipient, and optionally in conjunction with a single or more otheractive substances in an appropriate dosage form.

Another object of the present invention are compounds of formula (I)according to the invention and/or physiologically acceptable saltsthereof for use in the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byBTK activity. Another preferred object of the invention concernscompounds of formula (I) according to the invention and/orphysiologically acceptable salts thereof for use in the prophylactic ortherapeutic treatment and/or monitoring of lupus. The prior teaching ofthe present specification concerning the compounds of formula (I),including any preferred embodiment thereof, is valid and applicablewithout restrictions to the compounds according to formula (I) and theirsalts for use in the prophylactic or therapeutic treatment and/ormonitoring of lupus.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order toboost the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The methods of the invention can also be used to reducethe likelihood of developing a disorder or even prevent the initiationof disorders associated with BTK activity in advance or to treat thearising and continuing symptoms.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously incurred disease.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. In certain embodiments, the inventionrelates to a medicament comprising at least one compound according tothe invention and/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orpreparations thereof (e.g. a pharmaceutical composition orpharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with BTK activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

In various embodiments, the active ingredient may be administered aloneor in combination with other treatments. A synergistic effect may beachieved by using more than one compound in the pharmaceuticalcomposition, i.e. the compound of formula (I) is combined with at leastanother agent as active ingredient, which is either another compound offormula (I) or a compound of different structural scaffold. The activeingredients can be used either simultaneously or sequentially.

Included herein are methods of treatment in which at least one chemicalentity provided herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor (TNF) antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib dnd/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

B-cells and B-cell precursors expressing BTK have been implicated in thepathology of B-cell malignancies, including, but not limited to, B-celllymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma),hairy cell lymphoma, multiple myeloma, chronic and acute myelogenousleukemia and chronic and acute lymphocytic leukemia.

BTK has been shown to be an inhibitor of the Fas/APO-1 (CD-95) deathinducing signaling complex (DISC) in B-lineage lymphoid cells. The fateof leukemia/lymphoma cells may reside in the balance between theopposing proapoptotic effects of caspases activated by DISC and anupstream anti-apoptotic regulatory mechanism involving BTK and/or itssubstrates (Vassilev et al., J. Biol. Chem. 1998, 274, 1646-1656).

It has also been discovered that BTK inhibitors are useful aschemosensitizing agents, and, thus, are useful in combination with otherchemotherapeutic drugs, in particular, drugs that induce apoptosis.Examples of other chemotherapeutic drugs that can be used in combinationwith chemosensitizing BTK inhibitors include topoisomerase I inhibitors(camptothecin or topotecan), topoisomerase II inhibitors (e.g.daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide,melphalan and BCNU), tubulin directed agents (e.g. taxol andvinblastine), and biological agents (e.g. antibodies such as anti CD20antibody, IDEC 8, immunotoxins, and cytokines).

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating agents: such as altretamine, bendamustine, busulfan,carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine,ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol,mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan,mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide,palifosfamide, pipobroman, trofosfamide, uramustine, TH-302⁴, VAL-083⁴;Platinum Compounds: such as carboplatin, cisplatin, eptaplatin,miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin,satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;DNA altering agents: such as amrubicin, bisantrene, decitabine,mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine,brostallicin, pixantrone, laromustine^(1,3);Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane,sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptiniumacetate, voreloxin;Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin,ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine,vindesine, vinflunine; fosbretabulin, tesetaxel;Antimetabolites: such as asparaginase³, azacitidine, calciumlevofolinate, capecitabine, cladribine, cytarabine, enocitabine,floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine,methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine,thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed,sapacitabine, tegafur^(2,3), trimetrexate;Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin,epirubicin, idarubicin, levamisole, miltefosine, mitomycin C,romidepsin, streptozocin, valrubicin, zinostatin, zorubicin,daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide,buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone,estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant,goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin,nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen,thyrotropin alfa, toremifene, trilostane, triptorelin,diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol,orteronel, enzalutamide^(1,3);Aromatase inhibitors: such as aminoglutethimide, anastrozole,exemestane, fadrozole, letrozole, testolactone; formestane;Small molecule kinase inhibitors: such as crizotinib, dasatinib,erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib,ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib,gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib,dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib,linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib,perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib,tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib,apatinib⁴, cabozantinib S-malate^(1,3), ibrutinib^(1,3), icotinib⁴,buparlisib², cipatinib⁴, cobimetinibi^(1,3), idelalisibi^(1,3),fedratinibi, XL-647⁴;Photosensitizers: such as methoxsalen³; porfimer sodium, talaporfin,temoporfin;Antibodies: such as alemtuzumab, besilesomab, brentuximab vedotin,cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab,tositumomab, trastuzumab, bevacizumab, pertuzumab^(2,3); catumaxomab,elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab,nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab,rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab,matuzumab, dalotuzumab^(1,2,3) onartuzumab^(1,3) racotumomabi,tabalumab^(1,3) EMD-525797⁴, nivolumab^(1,3). Cytokines: such asaldesleukin, interferon alfa², interferon alfa2a³, interferonalfa2b^(2,3); celmoleukin, tasonermin, teceleukin, oprelvekin^(1,3),recombinant interferon beta-1a⁴; Drug Conjugates: such as denileukindiftitox, ibritumomab tiuxetan, iobenguane I123, prednimustine,trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin,aflibercept; cintredekin besudotox, edotreotide, inotuzumab ozogamicin,naptumomab estafenatox, oportuzumab monatox, technetium (99mTc)arcitumomabi^(1,3), vintafolide^(1,3);Vaccines: such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴,rindopepimut³, troVax⁴, MGN-1601⁴, MGN-1703⁴; andMiscellaneous: alitretinoin, bexarotene, bortezomib, everolimus,ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine,mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel³,sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin,vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide,entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib,lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin,pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat,thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar,gendicine⁴, picibanil⁴, reolysin⁴, retaspimycin hydrochloride^(1,3),trebananib^(2,3), virulizin⁴, carfilzomibi³, endostatin⁴, immucothel⁴,belinostat³, MGN-1703⁴.(¹Prop. INN (Proposed International Nonproprietary Name); ² Rec. INN(Recommended International Nonproprietary Names); ³ USAN (United StatesAdopted Name); ⁴ no INN).

In another aspect, the invention provides for a kit consisting ofseparate packs of an effective amount of a compound according to theinvention and/or pharmaceutically acceptable salts, derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally, an effective amount of a further activeingredient. The kit comprises suitable containers, such as boxes,individual bottles, bags or ampoules. The kit may, for example, compriseseparate ampoules, each containing an effective amount of a compoundaccording to the invention and/or pharmaceutically acceptable salts,derivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and an effective amount of a further activeingredient in dissolved or lyophilized form.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment is administered afterone or more symptoms have developed. In other embodiments, treatment isadministered in the absence of symptoms. For example, treatment isadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment is also continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

The compounds and compositions, according to the method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided above. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention are administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 100mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms optionally contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions are formulated according to the known art usingsuitable dispersing or wetting agents and suspending agents. The sterileinjectable preparation are also a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This is accomplished by the useof a liquid suspension of crystalline or amorphous material with poorwater solubility. The rate of absorption of the compound then dependsupon its rate of dissolution that, in turn, may depend upon crystal sizeand crystalline form. Alternatively, delayed absorption of aparenterally administered compound form is accomplished by dissolving orsuspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form also optionally comprises buffering agents.

Solid compositions of a similar type are also employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype are also employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms optionally also comprisebuffering agents. They optionally contain opacifying agents and can alsobe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as required. Ophthalmicformulation, ear drops, and eye drops are also contemplated as beingwithin the scope of this invention. Additionally, the present inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms can be made by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting BTK activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting BTK, or a mutant thereof, activity in a biological sample ina positive manner, comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

The compounds of the invention are useful in-vitro as unique tools forunderstanding the biological role of BTK, including the evaluation ofthe many factors thought to influence, and be influenced by, theproduction of BTK and the interaction of BTK. The present compounds arealso useful in the development of other compounds that interact with BTKsince the present compounds provide important structure-activityrelationship (SAR) information that facilitate that development.Compounds of the present invention that bind to BTK can be used asreagents for detecting BTK in living cells, fixed cells, in biologicalfluids, in tissue homogenates, in purified, natural biologicalmaterials, etc. For example, by labeling such compounds, one canidentify cells expressing BTK. In addition, based on their ability tobind BTK, compounds of the present invention can be used in in-situstaining, FACS (fluorescence-activated cell sorting), sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE), ELISA(enzyme-linked immunoadsorptive assay), etc., enzyme purification, or inpurifying cells expressing BTK inside permeabilized cells. The compoundsof the invention can also be utilized as commercial research reagentsfor various medical research and diagnostic uses. Such uses can includebut are not limited to: use as a calibration standard for quantifyingthe activities of candidate BTK inhibitors in a variety of functionalassays; use as blocking reagents in random compound screening, i.e. inlooking for new families of BTK ligands, the compounds can be used toblock recovery of the presently claimed BTK compounds; use in theco-crystallization with BTK enzyme, i.e. the compounds of the presentinvention will allow formation of crystals of the compound bound to BTK,enabling the determination of enzyme/compound structure by x-raycrystallography; other research and diagnostic applications, wherein BTKis preferably activated or such activation is conveniently calibratedagainst a known quantity of an BTKinhibitor, etc.; use in assays asprobes for determining the expression of BTK in cells; and developingassays for detecting compounds which bind to the same site as the BTKbinding ligands.

The compounds of the invention can be applied either themselves and/orin combination with physical measurements for diagnostics of treatmenteffectiveness. Pharmaceutical compositions containing said compounds andthe use of said compounds to treat BTK-mediated conditions is apromising, novel approach for a broad spectrum of therapies causing adirect and immediate improvement in the state of health, whether inhuman or animal. The orally bioavailable and active new chemicalentities of the invention improve convenience for patients andcompliance for physicians.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Modulation of BTK, or a mutant thereof, activity in a biological sampleis useful for a variety of purposes that are known to one of skill inthe art. Examples of such purposes include, but are not limited to,blood transfusion, organ transplantation, biological specimen storage,and biological assays.

Exemplification General Conditions and Analytical Methods

As depicted in the Examples below, in certain exemplary embodiments,compounds were prepared according to the following general procedures.It will be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

The symbols and conventions used in the following descriptions ofprocesses, schemes, and examples are consistent with those used in thecontemporary scientific literature, for example, the Journal of theAmerican Chemical Society or the Journal of Biological Chemistry.

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions were conducted at room temperatureunless otherwise noted. All compounds of the present invention weresynthesized by processes developed by the inventors.

¹H-NMR spectra were recorded on a Bruker Avance III 400 MHz. Chemicalshifts are expressed in parts per million (ppm, δ units). Couplingconstants are in units of Hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), or br (broad).

Mass spectra were obtained on Waters Acquity UPLC/MS systems, usingeither Atmospheric Chemical Ionization (APCI) or Electrospray Ionization(ESI). Column: XBridge C8, 3.5 μm, 4.6×50 mm; Solvent A: water+0.1% FA;Solvent B: CAN; Flow: 0.8 ml/min; Gradient: 15-95% B over 1.2 minutesmin.

HPLC data were obtained using Agilent 1100 series HPLC from Agilenttechnologies using XBridge column (C8, 3.5 μm, 4.6×50 mm). Solvent A:water+0.1% TFA; Solvent B: ACN; Flow: 2 ml/min; Gradient: 0 min: 5% B, 8min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min 5% B.

The microwave reactions were conducted using Biotage Initiator MicrowaveSynthesizer using standard protocols that are known in the art.

Some abbreviations that may appear in this application are as follows:

Aq. Aqueous BBFO Broad band fluorine observation BrettPhos2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl δ chemical shift d deuterium or doublet dddoublet of doublets DCM dichloromethane DIPEA diisopropylethylamine DMFdimethylformamide DMSO dimethylsulfoxide dppf1,1′-bis(diphenylphosphino)ferrocene eq. equivalent ES electrospray hhour ¹H proton HPLC high pressure liquid chromatography IR infrared Jcoupling constant K kelvin LC liquid chromatography m Multiplet or metaM molecular ion Me methyl MHz Megahertz min minute mL milliliter MS massspectrometry m/z mass-to-charge ratio N Normality (equivalent per liter)NMR nuclear magnetic resonance Pet petroleum RBF Round Bottom Flask RTroom temperature RuPhos2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl s singlet TFATrifluoroacetic acid THF tetrhydrofuran TLC thin layer chromatographyUFLC Ultra fast liquid chromatography UV ultraviolet V Volume VTVariable temperature

Compound numbers utilized in the Examples below correspond to compoundnumbers set forth supra.

(4E)-5-(3-bromophenyl)pent-4-enoic acid (Step 1): In a 250-mL roundbottom flask purged and maintained with an inert atmosphere of nitrogen,to a solution of (3-carboxypropyl)triphenylphosphanium bromide (23.26 g,51.5 mmol, 1.00 equiv) in DMSO (200 mL) was added sodium hydride (60% inoil, 5.4 g, 135.0 mmol, 2.63 equiv) at 0° C. The resulting mixture wasstirred for 1 h at 25° C., and then was added by 3-bromobenzaldehyde (10g, 51.4 mmol, 1.00 equiv) in batches. The reaction mixture was allowedto warm up to 30° C. and stirred for another 16 h. When the reaction wasdone, it was quenched by the addition of water (200 mL) and the pH valueof the resulting mixture was adjusted to ˜1 with hydrogen chloridesolution (2 N). The mixture was then extracted with ethyl acetate (3×100mL), and the combined organic layers were washed with brine, dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified in a silica gel column eluting with ethyl acetate in petroleumether (10% to 80% gradient) to afford (4E)-5-(3-bromophenyl)pent-4-enoicacid as yellow oil (13.8 g, 90%). MS: m/z=253.1 [M−H]⁻

5-(3-Bromophenyl)pentanoic acid (Step 2): In a 500-mL round bottomflask, to a solution of (4E)-5-(3-bromophenyl)pent-4-enoic acid (16.2 g,63.5 mmol, 1.00 equiv) and AcOH (2 mL, 34.9 mmol, 0.82 equiv) in ethylacetate (200 mL) was added Pd/C (10%, 6 g) under nitrogen atmosphere.The reaction flask was vacuumed and flushed with hydrogen. The reactionmixture was hydrogenated at room temperature for 16 hours under hydrogenatmosphere using a hydrogen balloon. After the reaction was done, thereaction mixture was filtered through a Celite pad and the filtrate wasconcentrated under reduced pressure to afford 5-(3-bromophenyl)pentanoicacid as light brown oil (16 g, 99%).

2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Step 3): In a250-mL round bottom flask, a mixture of 5-(3-bromophenyl)pentanoic acid(5.4 g, 21.0 mol, 1 equiv) in polyphosphoric acid (60 mL) was stirredovernight at 130° C. After the reaction was done, the reaction mixturewas cooled to 0° C. and quenched by the addition of sat. NaHCO₃ solutionslowly. The resulting mixture was extracted with EtOAc (3×100 mL), andthe combined organic layers were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column eluting with ethyl acetate in petroleumether (1% to 10% gradient) to afford2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one as brown oil (3 g,53.8%). m/z=238.9 [M+H]⁺

2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine (Step 4): In a250-mL round bottom flask purged and maintained with an inert atmosphereof nitrogen, 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (2.7 g,11.3 mol, 1 equiv), NH₄OAc (17.46 g, 226.5 mmol, 20.0 equiv) and NaBH₃CN(3.6 g, 57.3 mmol, 5.07 equiv) were mixed in i-PrOH (60 mL) at roomtemperature. The resulting mixture was stirred overnight at 80° C. Whenthe reaction was done, it was quenched by the addition of NaOH solution(1 N, 100 mL) and the mixture was extracted with DCM (3×100 mL). Thecombined organic layers were washed by brine, dried over sodium sulfateand concentrated under reduced pressure to afford2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine as brown oil (2.7g, 90%). m/z=240.0 [M+H]⁺

tert-butylN-[2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate (Step5): In a 250-mL round bottom flask, to a solution of2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine (3 g, 11.2 mmol, 1equiv) and TEA (1.27 g, 11.3 mmol, 1.00 equiv) in dichloromethane (30mL) was added (Boc)₂O (2.74 g, 11.3 mmol, 1.0 equiv) at 0° C. Theresulting solution was stirred for 16 h at 25° C. When the reaction wasdone, it was quenched by the addition of water (10 mL) and the mixturewas extracted with dichloromethane (3×20 mL). The combined organiclayers were washed by brine, dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified in a silica gel columneluting with dichloromethane in petroleum ether (5% to 50% gradient) toafford tert-butylN-[2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate as brownsolid (2.5 g, 58.8%). MS: m/z=284.0 [M+H−56]⁻

tert-butylN-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(Step 6): In a 250-mL round bottom flask purged and maintained with aninert atmosphere of nitrogen, to a stirring solution of tert-butylN-[2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate (2.25 g,6.6 mol, 1 equiv) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2.8 g, 10.5 mmol, 1.58 equiv) in dioxane (40 mL) were added Pd(dppf)Cl₂CH₂Cl₂ (0.60 g, 0.73 mmol, 1.58 equiv) and KOAc (1.45 g, 14.0 mmol, 2.12equiv) at room temperature. The resulting mixture was stirred at 100° C.for 2 h. After the reaction was done, the reaction mixture was filteredto remove insoluble solids and the filtrate was concentrated underreduced pressure to give tert-butylN-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate as black oil (2.84 g, crude). MS: m/z=388.0 [M+H]⁺.

tert-butylN-[2-(2-amino-3-nitropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(Step 7): In a 250-mL round bottom flask purged and maintained with aninert atmosphere of nitrogen, to a solution of tert-butylN-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(2.56 g, 6.60 mol, 1 equiv) and 4-chloro-3-nitropyridin-2-amine (1.27 g,6.95 mol, 1.05 equiv) in dioxane (30 mL) and water (3 mL) were addedPd(PPh₃)₂Cl₂ (0.52 g, 0.70 mmol, 0.11 equiv) and Na₂CO₃ (2.34 g, 20.97mmol, 3.18 equiv) at room temperature. The resulting mixture was stirredat 100° C. for 16 h. After the reaction was done, the reaction mixturewas filtered through a Celite pad and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columneluting with ethyl acetate in petroleum ether (5% to 30% gradient) toafford tert-butylN-[2-(2-amino-3-nitropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamateas brown oil (3.5 g, 93.2%). MS: m/z=399.1 [M+H]⁺.

tert-butylN-[2-(2,3-diaminopyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(Step 8): To a solution of tert-butylN-[2-(2-amino-3-nitropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(5 g, 11.29 mol, 1 equiv, 90%) in 200 mL MeOH was added Pd/C (10%, 2.5g) under nitrogen atmosphere. The mixture was hydrogenated at roomtemperature for 16 hours under hydrogen atmosphere using a hydrogenballoon, filtered through a Celite pad and concentrated under reducedpressure to give tert-butylN-[2-(2,3-diaminopyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamateas a brown oil (4.6 g, 77.38%). MS: m/z=369.1 [M+H]⁺.

tert-butylN-(2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(Step 9): In a 250-mL round bottom flask purged and maintained with aninert atmosphere of nitrogen, to a stirring solution of tert-butylN-[2-(2,3-diaminopyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(2.73 g, 7.4 mmol, 1 equiv) and3,5-dimethyl-1-(propan-2-yl)-1H-pyrazole-4-carbaldehyde (1.23 g, 7.0mmol, 0.95 equiv) in DMF (75 mL) was added 4-methylbenzene-1-sulfonicacid (0.18 g, 0.99 mmol, 0.13 equiv) at room temperature. The resultingmixture was stirred for 16 h at 100° C. After the reaction was done, thereaction mixture was concentrated under reduced pressure. The residuewas purified by silica gel column eluting with methanol in DCM (1% to10% gradient) to afford tert-butylN-(2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamateas brown oil (2.16 g, 56.6%). MS: m/z=515.1[M+H]⁺.

2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine(Step 10): At room temperature, tert-butylN-(2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate(4.8 g, 8.14 mmol, 1 equiv) was added to a solution of HCl in MeOH (4 M,40 mL, 160 mmol). The resulting mixture was stirred for 1 h at roomtemperature, and then was concentrated under reduced pressure. Theresidue was purified by reverse phase flash chromatography eluting withMeOH in water (10% to 50% gradient in 60 min) to afford2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine(2.5 g, 66.68%) as a brown solid. MS: m/z=415.6 [M+H]⁺.

3-tert-butyl-N-[(5R)-2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide(Step 11): In a 100-mL round bottom flask, to a solution of12-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine(1.8 g, 4.3 mmol, 1 equiv) and TEA (2.44 g, 22.9 mmol, 5.28 equiv) inMeOH (30 mL) was added methyl3-tert-butyl-1,2,4-oxadiazole-5-carboxylate (4.0 g, 21.7 mmol, 5.00equiv) at room temperature. The resulting solution was stirred for 16 hat 50° C. When the reaction was done, it was quenched by the addition ofwater (20 mL) and the mixture was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine, dried oversodium sulfate and concentrated under reduced pressure. The residue wasfirst purified in a silica gel column eluting with ethyl acetate inpetroleum ether (10% to 90% gradient) to afford the product as a mixtureof two enantiomers, which was further separated and purified bychiral-HPLC with the following conditions: column, CHIRALPAK IC-33×100mm 3 um; mobile phase, methanol (with 20 mM NH₃.H₂O); detector, 220/254nm.3-tert-butyl-N-[(5R)-2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamidewas obtained as white solid (549.3 mg, 49.7%). HPLC: 98.9% purity. MS:m/z=567.4 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): δ 12.78 (s, 1H), 9.99(d, J=8.1 Hz, 1H), 8.31-8.25 (m, 2H), 8.18 (d, J=8.0 Hz, 1H), 7.53 (d,J=5.3 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 5.32-5.27 (m, 1H), 4.60-4.56 (m,1H), 2.99-2.98 (m, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 1.98-1.81 (m, 6H),1.42-1.40 (m, 15H).

Example 2

3,5-dimethyl-1-(propan-2-yl)-1H-pyrazole-4-carbaldehyde (Step 1): In a500-mL round-bottom flask, to a solution of3,5-dimethyl-1H-pyrazole-4-carbaldehyde (8 g, 58.00 mmol, 1.00 equiv)and 2-iodopropane (14.17 g, 75.02 mmol, 1.29 equiv) in MeCN (160 mL) wasadded Cs₂CO₃ (27.17 g, 75.05 mmol, 1.29 equiv) at room temperature. Theresulting solution was stirred overnight at 50° C. After the reactionwas done, the reaction mixture was filtered to remove insoluble solidsand the filtrate was concentrated under reduced pressure. The residuewas purified in a silica gel column eluting with ethyl acetate inpetroleum ether (5% to 25% gradient) to give3,5-dimethyl-1-(propan-2-yl)-1H-pyrazole-4-carbaldehyde as a lightyellow solid (9.5 g, 89%). MS: m/z=167.0 [M+H]⁺

4-[5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]pyridine-2,3-diamine(Step 2): At room temperature, tert-butylN-[2-(2,3-diaminopyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(1.0 g, 2.44 mmol, 1 equiv) was added to a solution of HCl in MeOH (4M,10 mL). The resulting mixture was stirred for 1 h at room temperature.After the reaction was done, the reaction mixture was concentrated underreduced pressure to give4-[5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]pyridine-2,3-diamine, HCl salt as brown oil (720 mg, crude) MS:m/z=269.0 [M+H]⁺.

N-[2-(2,3-diaminopyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide(Step 3): In a 50-mL round-bottom flask, to a solution of4-[5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]pyridine-2,3-diamine,HCl salt (700 mg, ˜2.35 mmol, 1 equiv) and TEA (1.20 g, 11.75 mmol, 5.02equiv) in MeOH (10 mL) was added methyl3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylate (1.28 g, 7.05mmol, 3.01 equiv) at room temperature. The resulting solution wasstirred for 16 h at 50° C. When the reaction was done, it was quenchedby the addition of water (20 mL) and the mixture was extracted withethyl acetate (3×100 mL). The combined organic layers were washed withbrine, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified in a silica gel column eluting withmethanol in dichloromethane (5% to 10% gradient) to affordN-[2-(2,3-diaminopyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamideas brown oil (1.0 g, 87% for two steps). MS: m/z=419.2 [M+H]⁺

N-[(5S)-2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide(Step 4) In a 50-mL round-bottom flask, to a solution ofN-[2-(2,3-diaminopyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide(1 g, 2.15 mmol, 1 equiv) and3,5-dimethyl-1-(propan-2-yl)-1H-pyrazole-4-carbaldehyde (398 mg, 2.15mmol, 1.00 equiv) in DMF (10.0 mL) was added p-toluenesulfonic acid (41mg, 0.21 mmol, 0.10 equiv) at room temperature. The resulting solutionwas stirred for 16 h at 100° C. After the reaction was done, thereaction mixture was concentrated under reduced pressure and the residuewas first purified by Prep-HPLC with the following conditions: column,XBridge Shield RP18 OBD Column, 30*150 mm, 5 um; mobile phase, ACN inwater (with 10 mM NH₄HCO₃ and 0.1% NH₃.H₂O), 50% to 62% gradient in 8min; detector, uv 220/254 nm. The obtained product is a racemic mixtureof two enantiomers, which was further separated and purified by chiralHPLC using the following conditions: Column, (R,R)Whelk-O 1, 21.1×250mm, 5 um; mobile phase, hexane/DCM (3:1) and EtOH (with 8 mM NH₃.H₂O),isocratic 50% EtOH in 16 min; Detector, UV, 254 nm.N-[(5S)-2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamidewas obtained as a white solid (92 mg, 67.6%). HPLC: 99.2% purity. MS:m/z=565.2 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): δ 12.76 (br s, 1H),9.90 (d, J=8.0 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.22 (d, J=1.9 Hz, 1H),8.17 (d, J=7.9 Hz, 1H), 7.51 (d, J=5.3 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H),5.28-5.23 (m, 1H), 4.59-4.55 (m, 1H), 2.96-2.90 (m, 2H), 2.55 (s, 3H),2.42 (s, 3H), 1.97-1.94 (m, 3H), 1.84-1.80 (m, 2H), 1.52 (s, 3H),1.39-1.30 (m, 7H), 1.26-1.24 (m, 2H), 1.03-1.00 (m, 2H).

Example 3

tert-butylN-[2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(Step 1): In a 100-mL round-bottom flask, to a solution of tert-butylN-[2-(2,3-diaminopyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(2 g, 4.89 mmol, 1.00 equiv) and 1,5-dimethyl-1H-pyrazole-3-carbaldehyde(670 mg, 5.13 mmol, 1.05 equiv) in N,N-dimethylformamide (40 mL) wasadded p-toluenesulfonic acid 4-methylbenzene-1-sulfonic acid (93 mg,0.54 mmol, 0.11 equiv) at room temperature. The resulting solution wasstirred for 2 h at 120° C. After the reaction was done, the reactionmixture was concentrated under reduced pressure. The residue waspurified in a silica gel column eluting with methanol in dichloromethane(5% to 10% gradient) to afford tert-butylN-[2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamateas brown oil (1.1 g, 48%). MS: m/z=473.3 [M+H]⁺.

2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine,HCl salt (Step 2): At room temperature, tert-butylN-[2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(1.1 g, 2.09 mmol, 1.00 equiv) was added to a solution of HCl in MeOH (4M, 10 mL, 40 mmol). The resulting mixture was stirred for 1 h at roomtemperature. After the reaction was done, the reaction mixture wasconcentrated under reduced pressure to give2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine,HCl salt as brown oil (800 mg, crude). MS: m/z=373.2[M+H]⁺.

5-tert-butyl-N-[2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide(Step 3): In a 50-mL round-bottom flask, to a solution of2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine,HCl salt (800 mg, ˜1.93 mmol, 1.00 equiv) and TEA (1.52 g, 15.02 mmol,7.77 equiv) in methanol (15 mL) was added methyl5-tert-butyl-1,3,4-oxadiazole-2-carboxylate (2 g, 9.77 mmol, 5.05 equiv)at room temperature. The resulting solution was stirred for 2 h at 50°C. When the reaction was done, it was quenched by the addition of water(20 mL) and the mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by prep-HPLC with the following conditions: column, XBridgePrep C18 OBD Column, 19×150 mm 5 um; mobile phase, ACN in water (with 10mM NH₄HCO₃ and 0.1% NH₃.H₂O), 25% to 49% gradient in 8 min; Detector, UV254 nm.5-tert-butyl-N-[2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamidewas obtained as an off-white solid (250 mg, 25%). HPLC: 96.5% purity.MS: m/z=525.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d6, ppm): δ 13.39 (br s,1H), 9.91 (d, J=8.1 Hz, 1H), 8.30 (d, J=5.2 Hz, 1H), 8.20 (dd, J=8.1,1.8 Hz, 1H), 8.07 (d, J=1.9 Hz, 1H), 7.49 (d, J=5.2 Hz, 1H), 7.40 (d,J=8.1 Hz, 1H), 6.80-6.74 (m, 1H), 5.35-5.23 (m, 1H), 3.88 (s, 3H),3.03-2.97 (m, 2H), 2.34 (s, 3H), 2.03-1.97 (m, 4H), 1.91-1.78 (m, 2H),1.45 (s, 9H).

Example 4

tert-butylN-(6-[2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(Step 1): In a 30-mL vial, tert-butylN-[6-(2,3-diaminopyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate(300 mg, 0.76 mmol, 1.00 equiv) and1-(propan-2-yl)-1H-pyrazole-4-carbaldehyde (120 mg, 0.78 mmol, 1.03equiv) were mixed in N,N-dimethylformamide (15 mL) at room temperature.The resulting solution was stirred overnight at 80° C. After thereaction was done, the reaction mixture was concentrated under reducedpressure. The residue was purified by flash chromatography eluting withmethanol in DCM (1% to 10% gradient) to afford tert-butylN-(6-[2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)carbamateas a yellow solid (220 mg, 40%). MS: m/z=473.4 [M+H]⁺.

6-[2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-amine,HCl salt (Step 2): At room temperature, tert-butylN-(6-[2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(220 mg, 0.31 mmol, 1.00 equiv) was added to a solution of HCl in MeOH(4 M, 5 mL, 20 mmol). The resulting mixture was stirred for 16 h at roomtemperature. After the reaction was done, the reaction mixture wasconcentrated under reduced pressure to give6-[2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-amine,HCl salt as yellow solid (180 mg, crude). MS: m/z=373.2[M+H]⁺.

3-tert-butyl-N-(6-[2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazole-5-carboxamide(Step 3): In a 50-mL round-bottom flask, to a solution of6-[2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-amine,HCl salt (180 mg, 0.30 mmol, 1.00 equiv) and TEA (120 mg, 1.42 mmol,3.93 equiv) in methanol (4 mL) was added methyl3-tert-butyl-1,2,4-oxadiazole-5-carboxylate (225 mg, 1.47 mmol, 4.04equiv) at 25° C. The resulting solution was stirred overnight at 25° C.When the reaction was done, it was quenched by the addition of water (20mL) and the mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by Prep-HPLC with the following conditions: column, XBridgePrep C18 OBD Column, 19×150 mm 5 um; mobile phase, acetonitrile in water(with 10 mM NH₄HCO₃ and 0.1% NH₃.H₂O), 45% to 65% gradient in 10 min;Detector, UV 254 nm.3-tert-butyl-N-(6-[2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazole-5-carboxamidewas obtained as a white solid (45 mg, 24.6% for two steps). HPLC: 97.8%purity. MS: m/z=525.2 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): δ 13.26(br s, 1H), 9.77 (d, J=8.7 Hz, 1H), 8.47 (s, 1H), 8.30 (s, 1H),8.27-8.04 (m, 3H), 7.46-7.33 (m, 2H), 5.30-5.24 (m, 1H), 4.61 (p, J=6.6Hz, 1H), 2.93-2.87 (m, 2H), 2.05-1.99 (m, 3H), 1.85-1.79 (m, 1H), 1.47(d, J=6.6 Hz, 6H), 1.36 (s, 9H).

Example 5

3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbaldehyde (Step1): In a 250-mL round-bottom flask, to a solution of3-methyl-1H-pyrazole-4-carbaldehyde (2.2 g, 18.98 mmol, 1.00 equiv) inDMF (40 mL) was added sodium hydride (60% in oil, 1.2 g, 30.0 mmol, 1.58equiv) at 0° C. The mixture was stirred for 1 h at room temperature, andthen was added by 4-bromooxane (4 g, 23.03 mmol, 1.21 equiv). Thereaction mixture was then stirred overnight at 120° C. When the reactionwas done, it was quenched by the addition of water (20 mL) and themixture was extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by reversephase flash chromatography eluting with MeOH in water (10% to 40%gradient in 60 min) to give a mixture of3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbaldehyde and5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbaldehyde asyellow oil (1.2 g, 1:1, 33%). MS: m/z=195.2 [M+H]⁺

4-[7-bromo-3H-imidazo[4,5-b]pyridin-2-yl]-3-methyl-1-(oxan-4-yl)-1H-pyrazole(Step 2): In a 25-mL round-bottom flask, to a solution of4-bromopyridine-2,3-diamine (500 mg, 2.53 mmol, 1.00 equiv, 95%) and3-methyl-1-(oxan-4-yl)-1H-pyrazole-4-carbaldehyde (520 mg, as a 1:1mixture with other regioisomer, total 2.54 mmol, 1.01 equiv) inN,N-dimethylformamide (10 mL) was added p-toluenesulfonic acid (46 mg,0.25 mmol, 0.10 equiv) at room temperature. The resulting mixture wasstirred for 3 days at 100° C. After the reaction was done, the reactionmixture was concentrated under reduced pressure and the residue waspurified by reverse phase flash chromatography eluting with withmethanol in dichloromethane (5% to 10% gradient) to afford the desiredsingle regioisomer4-[7-bromo-3H-imidazo[4,5-b]pyridin-2-yl]-3-methyl-1-(oxan-4-yl)-1H-pyrazoleas a white solid (200 mg, 21%). MS: m/z=362.0[M+H]⁺.

Tert-butylN-(6-[2-[3-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(Step 3): In a 50-mL microwave vail purged and maintained with an inertatmosphere of nitrogen, to a stirred mixture of tert-butylN-[6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate(200 mg, 0.48 mmol, 1.00 equiv) and4-[7-bromo-3H-imidazo[4,5-b]pyridin-2-yl]-3-methyl-1-(oxan-4-yl)-1H-pyrazole(160 mg, 0.40 mmol, 0.82 equiv) in dioxane (10 mL) and water (1 mL) wereadded Pd(dppf)Cl₂.CH₂Cl₂ (37 mg, 0.04 mmol, 0.09 equiv) and Cs₂CO₃ (578mg, 1.69 mmol, 3.50 equiv) at room temperature. The reaction mixture wasirradiated with microwave for 4 h at 110° C. The mixture was allowed tocool down to room temperature and concentrated under reduced pressure.The residue was purified by silica gel column eluting with methanol inDCM (1% to 10% gradient) to afford tert-butylN-(6-[2-[3-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)carbamateas a yellow solid (250 mg, 88%). MS: m/z=529.3 [M+H]⁺

6-[2-[3-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-amine,HCl salt (Step 4): A solution of tert-butylN-(6-[2-[3-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(250 mg, 0.43 mmol, 1.00 equiv) and HCl in MeOH (4 M, 5 mL, 200 mmol)was stirred for 16 h at room temperature. After the reaction was done,the reaction mixture was concentrated under reduced pressure to give6-[2-[3-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-amine,HCl salt as yellow solid (200 mg, crude). MS: m/z=429.2[M+H]⁺.

3-tert-butyl-N-(6-[2-[3-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazole-5-carboxamide(Step 5): In a 25-mL round-bottom flask, to a solution of6-[2-[3-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-amine(200 mg, ˜0.43 mmol, 1.00 equiv) and TEA (283 mg, 2.66 mmol, 6.18 equiv)in methanol (10 mL) was added methyl3-tert-butyl-1,2,4-oxadiazole-5-carboxylate (500 mg, 2.58 mmol, 6 equiv)at room temperature. The resulting solution was stirred for 16 h at 50°C. When the reaction was done, it was quenched by the addition of water(20 mL) and the mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. The crude product waspurified by prep-HPLC with the following conditions: column, XBridgePrep C18 OBD Column, 19×150 mm 5 um; mobile phase, ACN in water (with 10mM NH₄HCO₃ and 0.1% NH₃.H₂O), 49% to 66% gradient in 9 min; detector, UV254 nm.3-tert-butyl-N-(6-[2-[3-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazole-5-carboxamidewas obtained as an off-white solid (120 mg, 43.6% for two steps). HPLC:99.2% purity. MS: m/z=581.4 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): δ13.11 (br s, 1H), 9.76 (d, J=9.0 Hz, 1H), 8.42 (s, 1H), 8.34 (s, 1H),8.26 (d, J=4.5 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.49 (d, J=4.8 Hz, 1H),7.38 (d, J=8.1 Hz, 1H), 5.30-5.25 (m, 1H), 4.42-4.39 (m, 1H), 4.01-3.98(m, 2H), 3.54-3.46 (m, 2H), 2.89-2.79 (m, 2H), 2.63 (s, 3H), 2.04-1.88(m, 8H), 1.36 (s, 9H).

Example 6

Tert-butylN-[2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(Step 1): In a 100-mL round bottom flask purged and maintained with aninert atmosphere of nitrogen, to a solution of tert-butylN-[2-(2,3-diaminopyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(1.3 g, 3.18 mmol, 1.00 equiv) and1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (488 mg, 3.36 mmol, 1.06equiv) in N,N-dimethylformamide (30 mL) was added4-methylbenzene-1-sulfonic acid (61 mg, 0.35 mmol, 0.11 equiv) at roomtemperature. The resulting mixture was stirred for 4 days at 100° C.After the reaction was done, the reaction mixture was concentrated underreduced pressure. The residue was purified by silica gel column elutingwith methanol in DCM (1% to 10% gradient) to afford tert-butylN-[2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamateas a brown solid (0.6 g, 39%). MS: m/z=487.4 [M+H]⁺.

2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine(Step 2): At room temperature, tert-butylN-[2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate(590 mg, 1.09 mmol, 1.00 equiv) was added to a solution of HCl in MeOH(4 M, 5 mL, 20 mmol). The resulting mixture was stirred for 16 h at roomtemperature. After the reaction was done, the reaction mixture wasconcentrated under reduced pressure to give tert-butylN-[2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]carbamate,HCl salt as yellow solid (400 mg, crude). MS: m/z=387.1 [M+H]⁺.

3-tert-butyl-N-[2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide(Step 3): In a 25-mL round-bottom flask, to a solution of2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine(440 mg, ˜1.02 mmol, 1.00 equiv) and TEA (576 mg, 5.69 mmol, 5.56equiv)) in methanol (5 mL) was added methyl3-tert-butyl-1,2,4-oxadiazole-5-carboxylate (1.05 g, 5.13 mmol, 5.01equiv) at room temperature. The resulting solution was stirred for 16 hat 50° C. When the reaction was done, it was quenched by the addition ofwater (20 mL) and the mixture was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine, dried oversodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 19×150 mm Sum; mobile phase, ACN in water(with 10 mM NH₄HCO₃ and 0.1% NH₃.H₂O), 50% to 53% gradient in 10 min;detector, uv 254 nm.3-tert-butyl-N-[2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamidewas obtained as a light brown solid. HPLC: 97.5% purity. MS: m/z=539.4[M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): δ 12.78 (br s, 1H), 9.98 (d,J=7.8 Hz, 1H), 8.28 (d, J=5.2 Hz, 1H), 8.26 (d, J=1.9 Hz, 1H), 8.17 (dd,J=8.1, 1.9 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H),5.32-5.23 (m, 1H), 3.76 (s, 3H), 2.98-2.96 (m, 2H), 2.54 (s, 3H), 2.41(s, 3H), 1.97-1.83 (m, 6H), 1.42 (s, 9H).

Example 7

6-bromo-1,2,3,4-tetrahydronaphthalen-1-amine1-(oxan-4-yl)-1H-pyrazole-4-carbaldehyde (Step 1): In a 250-mL roundbottom flask purged and maintained with an inert atmosphere of nitrogen,to a suspension of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (4.5 g,19.99 mmol, 1.00 equiv) in 2-propanol (55 mL) was added NaBH₃CN (6.3 g,100.25 mmol, 5.01 equiv) and ammonium acetate (30.6 g, 396.98 mmol,19.86 equiv) in sequence at room temperature. The reaction mixture wasthen stirred at room temperature for 4 hour, then heated up to refluxand stirred overnight under reflux. The reaction mixture was then cooleddown to room temperature and poured into cold H₂O (500 ml). The pH valueof the resulting mixture was adjusted to 12 with sodium hydroxidesolution (1 N) and the mixture were extracted with DCM (3×30 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under to give 6-bromo-1,2,3,4-tetrahydronaphthalen-1-amineas yellow oil (4.5 g, crude). MS: m/z=226.0[M+H]⁺

Tert-butyl N-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (Step3): In a 50-mL round-bottom flask, to a solution of6-bromo-1,2,3,4-tetrahydronaphthalen-1-amine (4.34 g, 19.17 mmol, 1.00equiv) and TEA (3.07 g, 30.33 mmol, 1.58 equiv) in dichloromethane (80mL) was added (Boc)₂O (6.65 g, 30.47 mmol, 1.59 equiv) at 0° C. Theresulting solution was stirred for 16 h at 25° C. After the reaction wasdone, it was quenched by the addition of water (10 mL) and the mixturewas extracted with dichloromethane (3×20 mL). The combined organiclayers were washed by brine, dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified in a silica gel columneluting with dichloromethane in petroleum ether (5% to 20% gradient) toafford tert-butyl N-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)carbamateas white oil (6.2 g, 95% for two steps). MS: m/z=269.9[M+H−56]⁻

Tert-butylN-[6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate(Step 3): In a 100-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen, to a solution of tert-butylN-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (6.20 g, 17.10mmol, 1.00 equiv) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(5.21 g, 20.52 mmol, 1.20 equiv) in 1,4-dioxane (62 mL) were added KOAc(3.71 g, 34.02 mmol, 1.99 equiv,), Pd(dppf)Cl₂.CH₂Cl₂ (1552.03 mg, 1.71mmol, 0.10 equiv) at room temperature. The resulting mixture was stirredat 110° C. for 16 h. T After the reaction was done, the reaction mixturewas filtered through a Celite pad and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columneluting with ethyl acetate in petroleum ether (5% to 20% gradient) toafford tert-butylN-[6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamateas a yellow solid (5.2 g, 81%). MS: m/z=396.1 [M+H]⁺.

Tert-butylN-[6-(2-amino-3-nitropyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate(Step 4): (The following reaction was done in 4 equivalent batches butcombined for purification) In each of the four 50-mL microwave vialspurged and maintained with an inert atmosphere of nitrogen,4-chloro-3-nitropyridin-2-amine (479.7 mg, 2.76 mmol, 0.80 equiv),tert-butylN-[6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate(1.50 g, 3.46 mmol, 1.00 equiv), sodium bicarbonate (580.6 mg, 6.91mmol, 2.00 equiv) and Pd(dppf)Cl₂.CH₂Cl₂ (313.56 mg, 0.35 mmol, 0.10equiv) were mixed in tetrahydrofuran (15.00 mL) and water (1.50 mL) wereadded at room temperature. The reaction mixture was irradiated withmicrowave for 30 min at 80° C. under N₂. The reaction was then quenchedby the addition of 20 mL water. The mixture was allowed to cool down toroom temperature. The reaction mixture was concentrated under reducedpressure. The residue of the four batches of reactions were combined andpurified by silica gel column eluting with methanol in DCM (1% to 10%gradient) to afford tert-butylN-[6-(2-amino-3-nitropyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamateas a yellow solid (3.5 g, 75%). MS: m/z=385.1[M+H]⁺

Tert-butylN-[6-(2,3-diaminopyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate(Step 5): In a 250-mL round-bottom flask, to a solution ofN-[6-(2-amino-3-nitropyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate(3.50 g, 7.74 mmol, 1.00 equiv) in ethanol (26 mL) and water (13 mL)were added iron powder (4.32 g, 77.36 mmol, 10.00 equiv) and NH₄Cl (8.28g, 154.79 mmol, 20.00 equiv) at room temperature. The resulting mixturewas stirred at 80° C. for 1 h. After the reaction was done, the reactionmixture was filtered through a Celite pad and the filtrate wasconcentrated under reduced pressure. The residue was diluted with water(100 mL) and the mixture was extracted with dichloromethane (3×200 mL).The combined organic layers were washed with brine (3×100 mL), driedover sodium sulfate and concentrated under reduced pressure to affordtert-butylN-[6-(2,3-diaminopyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamateas a yellow solid (2.8 g, 92%). MS: m/z=355.1[M+H]⁺

Tert-butylN-(6-[2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(Step 6): In a 20-mL vial, to a solution of tert-butylN-[6-(2,3-diaminopyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate(1 g, 2.54 mmol, 1.00 equiv) in N,N-dimethylformamide (11 mL) was added5-methyl-1-(propan-2-yl)-1H-pyrazole-4-carbaldehyde (433.68 mg as a 1:1mixture with other regioisomer, total 2.56 mmol, 1.01 equiv) at roomtemperature. The resulting mixture was stirred for 3 days at 100° C.After the reaction was done, the reaction mixture was concentrated underreduced pressure and the residue was purified. The residue was purifiedby silica gel column eluting with methanol in DCM (1% to 10% gradient)to afford the desired single regioisomer tert-butylN-(6-[2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)carbamateas a yellow solid (350 mg, 29%). MS: m/z=487.2[M+H]⁺

6-[2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-amine,HCl salt (Step 7): A solution of tert-butylN-(6-[2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(180 mg, 0.33 mmol, 1.0 eq) and HCl in MeOH (5 mL, 4M) was stirred for16 h at room temperature. After the reaction was done, the reactionmixture was concentrated under reduced pressure to give6-[2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-amine,HCl salt as yellow solid, which was used in next step without furtherpurification (150 mg, crude). MS: m/z=387.1[M+H]⁺.

3-tert-butyl-N-(6-[2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazole-5-carboxamide(Step 8): In a 100-mL vial, to a solution of6-[2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-amine,HCl salt (150 mg, ˜0.33 mmol, 1.00 equiv) and TEA (180 mg, 1.78 mmol,5.30 equiv) in methanol (3 mL) was added methyl3-tert-butyl-1,2,4-oxadiazole-5-carboxylate (357 mg, 1.74 mmol, 5.27equiv) at room temperature. The resulting solution was stirred for 2days at 50° C. When the reaction was done, it was quenched by theaddition of water (20 mL) and the mixture was extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine,dried over sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by Prep-HPLC with the following conditions:column, XBridge Prep C18 OBD Column, 19×150 mm 5 um; mobile phase, ACNin water (with 10 mM NH₄HCO₃ and 0.1% NH₃.H₂O), 55% to 67% gradient in10 min; detector, UV 254 nm.3-tert-butyl-N-(6-[2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazole-5-carboxamidewas obtained as a white solid (100 mg, 56% for 2 steps). HPLC: 100%purity. MS: m/z=539.2 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d6, ppm): δ 13.19(br s, 1H), 9.77 (d, J=8.7 Hz, 1H), 8.28-8.25 (m, 2H), 8.16-8.11 (m,2H), 7.48 (d, J=5.2 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 5.28-5.27 (m, 1H),4.66-4.62 (m, 1H), 2.91-2.85 (m, 2H), 2.81 (s, 3H), 2.06-1.95 (m, 3H),1.84-1.82 (m, 1H), 1.43-1.36 (m, 15H).

Example 8

7-Bromo-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine(Step 1) To a reaction vial with stirbar was added a mixture of2,3-diamino-4-bromopyridine (1.10 g; 5.85 mmol; 1.00 eq.),1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid (0.99 g; 6.44 mmol; 1.10eq.) and polyphosphoric acid (5.34 ml). The reaction mixture was heatedat 130° C. overnight. Ice was added into the vial with stirring until aclear brown solution was obtained. The solution was transferred to a 250mL flask with some water rinses (˜25 mL) and cooled to room temperature.NaOH (21.06 g; 263.26 mmol; 45.00 eq.) solid was added to neutralize thereaction mixture to pH 8. Sodium hydroxide was added portion wise sothat the temperature of the aqueous solution did not exceed 50° C. Theresulting suspension was stirred in an icebath for 30 min then theprecipitate was collected by filtration, washed with water (2×20 mL),and dried under high vacuum at 35° C. overnight to yield 967 mg (54%) ofthe title compound. LC/MS: 306 (M+H).

{2-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-carbamicacid tert-butyl ester (Step 2). In a microwave vial with a stirbar wasadded7-Bromo-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine(360.00 mg; 1.18 mmol; 1.00 eq.),[2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl]-carbamicacid tert-butyl ester (500.97 mg; 1.29 mmol; 1.10 eq.), Sodium carbonate(373.88 mg; 3.53 mmol; 3.00 eq.), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complexwith dichloromethane (144.04 mg; 0.18 mmol; 0.15 eq.). The vial wassealed then evacuated/N₂-backfilled (3×). EtOH (5.40 ml; 15.00 V) andwater (0.54 ml; 1.50 V) were added via syringe and the vial wasevacuated/N₂-backfilled (3×) again. The mixture was stirred in a 80degrees C. heating block overnight. LCMS-5 after 3 hr indicated thereaction was complete. The reaction was diluted with DCM (10 mL);filtered through a celite plug; and concentrated on SiO2. Purified viaflash chromatography (Biotage): 25 g column using 50% EA/Hex isocraticfor 5 min then ramped to 100% EA over 10 min. Ran 100% EA isocratic for10 min and then ramped 0-10% MeOH/EA over 10 min at a flow rate of 25mL/min. The product began eluting ˜5% MeOH/EA. Combined and concentratedproduct fractions to yield 513 mg (90%) of the title compound as anorange solid foam. LCMS: 487 (M+H).

2-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (Step 3) In a round bottom flask with magnetic stirbar{2-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-carbamicacid tert-butyl ester (510.00 mg; 0.94 mmol; 1.00 eq.) was dissolved inmethanol, anhydrous (7.65 ml; 15.00 V). 2.0M hydrogen chloride indiethyl ether (4.72 ml; 9.43 mmol; 10.00 eq.) was then added to thestirring solution. The reaction was stirred at room temperatureovernight. The reaction was diluted with Et2O (50 mL) and the resultingsuspension quickly became an oil. Concentrated to dryness and placedunder high vacuum overnight. Assumed 100% yield of the title compound.LCMS: 387 (M+H).

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide(Step 4) In a reaction vial with magnetic stirbar a stirring solution of2-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (466.12 mg; 0.94 mmol; 1.00 eq.),5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid (319.91 mg; 1.88 mmol;2.00 eq.), DIPEA (0.82 ml; 4.70 mmol; 5.00 eq.), DCM (9.32 ml; 20.00 V),and DMF (0.60 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (1.40ml; 2.35 mmol; 2.50 eq.). The reaction mixture was stirred at roomtemperature overnight. The mixture was concentrated, re-dissolved in EA(75 mL) and water (50 mL). The layers were separated, and the EA layerwas washed with water (2×30 mL) and brine (1×30 mL); dried (Na₂SO₄);filtered; and concentrated on KPNH silica. Purified via flashchromatography (Biotage): 28 g KPNH column using 50% EA/Hex isocraticfor 5 min then ramped to 100% EA over 5 min at a flow rate of 30 mL/min.Yielded 59 mg (11%) of the title compound as a white solid. LCMS: 539(M+H). ¹H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.54 (d, J=8.1 Hz,1H), 8.29 (d, J=5.2 Hz, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.16 (dd, J=8.1,1.9 Hz, 1H), 7.52 (d, J=5.3 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.29 (t,J=8.6 Hz, 1H), 3.75 (s, 3H), 2.98 (d, J=9.6 Hz, 2H), 2.55 (s, 3H), 2.42(s, 3H), 1.97 (d, J=12.1 Hz, 3H), 1.83 (q, J=9.5 Hz, 2H), 1.46 (s, 9H),1.41-1.30 (m, 1H).

Example 9

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide:The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded18 mg (31%) of the title compound. LCMS: 539 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 12.75 (s, 1H), 9.54 (d, J=8.1 Hz, 1H), 8.29 (d, J=5.2 Hz,1H), 8.25 (d, J=1.9 Hz, 1H), 8.16 (dd, J=8.1, 1.9 Hz, 1H), 7.52 (d,J=5.3 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.29 (t, J=8.6 Hz, 1H), 3.75 (s,3H), 2.98 (d, J=9.6 Hz, 2H), 2.55 (s, 3H), 2.42 (s, 3H), 1.97 (d, J=12.1Hz, 3H), 1.83 (q, J=9.5 Hz, 2H), 1.46 (s, 9H), 1.41-1.30 (m, 1H).

Example 10

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(S)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide:The desired compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded19 mg (32%) of the title compound. LCMS: 539 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 12.75 (s, 1H), 9.54 (d, J=8.1 Hz, 1H), 8.29 (d, J=5.2 Hz,1H), 8.25 (d, J=1.9 Hz, 1H), 8.16 (dd, J=8.1, 1.9 Hz, 1H), 7.52 (d,J=5.3 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.29 (t, J=8.6 Hz, 1H), 3.75 (s,3H), 2.98 (d, J=9.6 Hz, 2H), 2.55 (s, 3H), 2.42 (s, 3H), 1.97 (d, J=12.1Hz, 3H), 1.83 (q, J=9.5 Hz, 2H), 1.46 (s, 9H), 1.41-1.30 (m, 1H).

Example 11

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide:In a reaction vial with magnetic stirbar a stirring solution of2-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (466.12 mg; 0.94 mmol; 1.00 eq.),5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid (316.12 mg;1.88 mmol; 2.00 eq.), DIPEA (818.66 μl; 4.70 mmol; 5.00 eq.), DCM (9.32ml; 20.00 V), and DMF (0.96 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (1.40ml; 2.35 mmol; 2.50 eq.). The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted with DCM (50 mL) andwashed with water (1×50 mL) and brine (1×25 mL). The organic layer wasthen dried (Na₂SO₄); filtered; and concentrated. The crude was dissolvedin DMSO (3 mL) and purified via prep HPLC (Interchim P4250; 30×150 mmC-18 column; 0.1% NH₄OH modified mobile phases (A=water, B=ACN);gradient 20-70% B over 20 min. Combined product fractions andlyophilized overnight to provide 420 mg (83%) of the title compound as awhite solid. LCMS: 537 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H),9.48 (d, J=8.1 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.24 (d, J=1.9 Hz, 1H),8.15 (dd, J=8.0, 1.9 Hz, 1H), 7.51 (d, J=5.2 Hz, 1H), 7.34 (d, J=8.1 Hz,1H), 5.28 (t, J=8.6 Hz, 1H), 3.75 (s, 3H), 2.97 (d, J=10.4 Hz, 2H), 2.55(s, 3H), 2.42 (s, 3H), 1.96 (d, J=11.0 Hz, 3H), 1.82 (q, J=9.6 Hz, 2H),1.57 (s, 3H), 1.42 (q, J=4.1 Hz, 2H), 1.36 (d, J=7.2 Hz, 1H), 1.19 (q,J=4.2 Hz, 2H).

Example 12

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded150 mg (38%) of the title compound. LCMS: 537 (M+H). ¹H NMR (400 MHz,DMSO-d₆) δ 12.75 (s, 1H), 9.48 (d, J=8.1 Hz, 1H), 8.29 (d, J=5.2 Hz,1H), 8.24 (d, J=1.9 Hz, 1H), 8.15 (dd, J=8.0, 1.9 Hz, 1H), 7.51 (d,J=5.2 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.28 (t, J=8.6 Hz, 1H), 3.75 (s,3H), 2.97 (d, J=10.4 Hz, 2H), 2.55 (s, 3H), 2.42 (s, 3H), 1.96 (d,J=11.0 Hz, 3H), 1.82 (q, J=9.6 Hz, 2H), 1.57 (s, 3H), 1.42 (q, J=4.1 Hz,2H), 1.36 (d, J=7.2 Hz, 1H), 1.19 (q, J=4.2 Hz, 2H).

Example 13

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{(S)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded152 mg (38%) of the title compound. LCMS: 537 (M+H). ¹H NMR (400 MHz,DMSO-d₆) δ 12.75 (s, 1H), 9.48 (d, J=8.1 Hz, 1H), 8.29 (d, J=5.2 Hz,1H), 8.24 (d, J=1.9 Hz, 1H), 8.15 (dd, J=8.0, 1.9 Hz, 1H), 7.51 (d,J=5.2 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.28 (t, J=8.6 Hz, 1H), 3.75 (s,3H), 2.97 (d, J=10.4 Hz, 2H), 2.55 (s, 3H), 2.42 (s, 3H), 1.96 (d,J=11.0 Hz, 3H), 1.82 (q, J=9.6 Hz, 2H), 1.57 (s, 3H), 1.42 (q, J=4.1 Hz,2H), 1.36 (d, J=7.2 Hz, 1H), 1.19 (q, J=4.2 Hz, 2H).

Example 14

{8-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-carbamicacid tert-butyl ester (Step 1) In a microwave vial with a stirbar wasadded7-Bromo-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine(440.00 mg; 1.15 mmol; 1.00 eq.),[8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl]-carbamicacid tert-butyl ester (492.34 mg; 1.26 mmol; 1.10 eq.), Sodium carbonate(365.57 mg; 3.45 mmol; 3.00 eq.), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complexwith dichloromethane (140.84 mg; 0.17 mmol; 0.15 eq.). The vial wassealed then evacuated/N₂-backfilled (3×). EtOH (8.80 ml; 20.00 V) andwater (0.88 ml; 2.00 V) were added via syringe and the vial wasevacuated/N₂-backfilled (3×) again. The mixture was stirred in an 80° C.heating block overnight. The reaction contents were concentrated onto asample of KP-NH silica gel. The sample was then loaded onto a 50 g KP-NHcolumn and the Biotage was run 50% to 100% EtOAc in Hexanes. The purefractions were combined and concentrated to obtain the title compound asa yellow solid. LC/MS: 489 (M+H).

8-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-ylaminehydrochloride (Step 2) In a reaction vial with magnetic stirbar{8-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-carbamicacid tert-butyl ester (350.00 mg; 0.72 mmol; 1.00 eq.) was dissolved inmethanol, anhydrous (5.25 ml; 15.00 V) and 4.0M hydrogen chloride indioxane (2.69 ml; 10.75 mmol; 15.00 eq.). The golden homogeneousreaction mixture was stirred at room temperature overnight. The reactionwas diluted with Et2O (˜25 mL) and stirred at room temperature for 30min. The reaction suspension was then filtered and the solids wererinsed with Et2O (2×10 mL). The solid was dried under high vacuumovernight to provide 308 mg (86%) of the title compound as a whitesolid. LCMS: 389 (M+H).

Step 3 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide(Step 3): In a reaction vial with magnetic stirbar a stirring solutionof8-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-ylaminehydrochloride (3) (150.00 mg; 0.30 mmol; 1.00 eq.),5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid (102.54 mg; 0.60 mmol;2.00 eq.), DIPEA (262.40 μl; 1.51 mmol; 5.00 eq.), DCM (3.00 ml; 20.00V), and DMF (0.75 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (448.40μl; 0.75 mmol; 2.50 eq.). The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted with DCM (50 mL) andwashed with water (1×50 mL) and brine (1×25 mL). The organic layer wasthen dried (Na₂SO₄); filtered; and concentrated. Dissolved in DMSO (4mL) and purified via prep HPLC (Interchim P4250; 30×250 mm C-18 column;0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient 25-75% Bover 20 min. The product fractions were combined, froze, and lyophilizedovernight. Yielded 132 mg (81%) of the title compound as a white solid.LCMS: 541 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 13.43 (s, 1H), 9.41 (d,J=8.4 Hz, 1H), 8.32 (d, J=5.2 Hz, 1H), 8.02 (s, 2H), 7.97 (d, J=2.4 Hz,1H), 7.48 (s, 1H), 7.39 (dd, J=8.4, 0.8 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H),5.34 (t, J=5.8 Hz, 1H), 4.66 (hept, J=6.7 Hz, 1H), 4.31 (d, J=12.1 Hz,1H), 3.85 (dd, J=11.8, 7.7 Hz, 1H), 2.09-1.96 (m, 4H), 1.53 (s, 3H),1.51 (s, 3H), 1.46 (s, 8H).

Example 15

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(R)-8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded55 mg (46%) of the title compound. LCMS: 541 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.43 (s, 1H), 9.41 (d, J=8.4 Hz, 1H), 8.32 (d, J=5.2 Hz,1H), 8.02 (s, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.39 (dd,J=8.4, 0.8 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 5.34 (t, J=5.8 Hz, 1H), 4.66(hept, J=6.7 Hz, 1H), 4.31 (d, J=12.1 Hz, 1H), 3.85 (dd, J=11.8, 7.7 Hz,1H), 2.09-1.96 (m, 4H), 1.53 (s, 3H), 1.51 (s, 3H), 1.46 (s, 8H).

Example 16

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(S)-8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded56 mg (46%) of the title compound. LCMS: 541 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.43 (s, 1H), 9.41 (d, J=8.4 Hz, 1H), 8.32 (d, J=5.2 Hz,1H), 8.02 (s, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.39 (dd,J=8.4, 0.8 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 5.34 (t, J=5.8 Hz, 1H), 4.66(hept, J=6.7 Hz, 1H), 4.31 (d, J=12.1 Hz, 1H), 3.85 (dd, J=11.8, 7.7 Hz,1H), 2.09-1.96 (m, 4H), 1.53 (s, 3H), 1.51 (s, 3H), 1.46 (s, 8H).

Example 17

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid{8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.In a reaction vial with magnetic stirbar a stirring solution of8-[2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-ylaminehydrochloride (3) (150.00 mg; 0.30 mmol; 1.00 eq.),5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid (102.54 mg; 0.60 mmol;2.00 eq.), DIPEA (262.40 μl; 1.51 mmol; 5.00 eq.), DCM (3.00 ml; 20.00V), and DMF (0.75 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (448.40μl; 0.75 mmol; 2.50 eq.). The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted with DCM (50 mL) andwashed with water (1×50 mL) and brine (1×25 mL). The organic layer wasthen dried (Na₂SO₄); filtered; and concentrated. Dissolved in DMSO (4mL) and purified via prep HPLC (Interchim P4250; 30×250 mm C-18 column;0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient 25-75% Bover 20 min. The product fractions were combined, froze, and lyophilizedovernight. Yielded 33 mg (20%) of the title compound as a white solid.LCMS: 541 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H), 9.77 (d,J=8.4 Hz, 1H), 8.31 (d, J=5.2 Hz, 1H), 8.02 (s, 2H), 7.96 (d, J=2.4 Hz,1H), 7.47 (s, 1H), 7.40 (d, J=7.9 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 5.32(d, J=7.8 Hz, 1H), 4.66 (p, J=6.7 Hz, 1H), 4.36 (d, J=12.1 Hz, 1H), 3.79(t, J=9.8 Hz, 1H), 2.03 (s, 4H), 1.52 (d, J=6.7 Hz, 6H), 1.43 (s, 9H).

Example 18

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid{(R)-8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded11 mg (41%) of the title compound. LCMS: 541 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.42 (s, 1H), 9.77 (d, J=8.4 Hz, 1H), 8.31 (d, J=5.2 Hz,1H), 8.02 (s, 2H), 7.96 (d, J=2.4 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J=7.9Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 5.32 (d, J=7.8 Hz, 1H), 4.66 (p, J=6.7Hz, 1H), 4.36 (d, J=12.1 Hz, 1H), 3.79 (t, J=9.8 Hz, 1H), 2.03 (s, 4H),1.52 (d, J=6.7 Hz, 6H), 1.43 (s, 9H).

Example 19

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid{(S)-8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded10 mg (37%) of the title compound. LCMS: 541 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.42 (s, 1H), 9.77 (d, J=8.4 Hz, 1H), 8.31 (d, J=5.2 Hz,1H), 8.02 (s, 2H), 7.96 (d, J=2.4 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J=7.9Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 5.32 (d, J=7.8 Hz, 1H), 4.66 (p, J=6.7Hz, 1H), 4.36 (d, J=12.1 Hz, 1H), 3.79 (t, J=9.8 Hz, 1H), 2.03 (s, 4H),1.52 (d, J=6.7 Hz, 6H), 1.43 (s, 9H).

Example 20

7-Bromo-2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine(Step 1) In a 250 mL RBF with stirbar was added4-Bromo-pyridine-2,3-diamine (5.000 g; 26.592 mmol; 1.00 eq.),1-Isopropyl-5-methyl-1H-pyrazole-4-carboxylic acid (4.920 g; 29.251mmol; 1.10 eq.), and polyphosphoric acid (11.905 ml). The flask washeated at 120° C. overnight. Cooled to 50° C. Added crushed ice to thereaction and added. NaOH (47.862 g; 1196.649 mmol; 45.00 eq.) portionwise. The contents were poured into a sep funnel and 300 mL of EtOAc wasadded. The aq layer was extracted 2×300 mL of EtOAc. The combinedorganics were then washed with 200 mL of brine and dried over Na₂SO₄.The solids were dried under high vacuum overnight to provide 3.80 g(45%) of the title compound as a brown crystalline solid. LCMS: 320(M+H).

{2-[2-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-carbamicacid tert-butyl ester (Step 2) In a microwave vial with a stirbar wasadded7-Bromo-2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine(1.26 g; 3.94 mmol; 1.00 eq.),[2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl]-carbamicacid tert-butyl ester (1.68 g; 4.33 mmol; 1.10 eq.), Sodium carbonate(1.25 g; 11.81 mmol; 3.00 eq.), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complexwith dichloromethane (482.05 mg; 0.59 mmol; 0.15 eq.). The vial wassealed then evacuated/N₂-backfilled (3×). EtOH (12.60 ml; 10.00 V) andwater (1.26 ml; 1.00 V) were added via syringe and the vial wasevacuated/N₂-backfilled (3×) again. The mixture was stirred in a 80° C.heating block overnight. The reaction was diluted with DCM (10 mL);filtered through a celite plug and concentrated on KPNH silica. Purifiedvia flash chromatography (Biotage): 50 g KPNH column using 50% EA/Hexisocratic for 5 min then ramped to 100% EA over 20 min at 50 mL/min. Theproduct fractions were combined and concentrated to provide 1.52 g (75%)of the title compound as a peach solid. LCMS: 501 (M+H).

2-[2-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (Step 3) In a round bottom flask with magnetic stirbar{2-[2-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-carbamicacid tert-butyl ester (1.60 g; 3.20 mmol; 1.00 eq.) was dissolved inmethanol, anhydrous (8.00 ml; 5.00 V) and 2.0M hydrogen chloride indiethyl ether (15.98 ml; 31.96 mmol; 10.00 eq.). The reaction wasstirred at room temperature overnight. The reaction was diluted withEt2O (100 mL) and stirred for 1 hr. The resulting suspension wasfiltered and the solids were washed with Et2O (2×25 mL). The solids weredried under high vacuum to yield 1.47 g (90%) of the title compound as apeach solid. LCMS: 401 (M+H).

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide(Step 4) In a reaction vial with magnetic stirbar a stirring solution of2-[2-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylamine(212.28 mg; 0.53 mmol; 1.00 eq.),5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid (180.38 mg; 1.06 mmol;2.00 eq.), DIPEA (0.28 ml; 1.59 mmol; 3.00 eq.), DCM (4.25 ml; 20.00 V),and DMF (0.60 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.79ml; 1.33 mmol; 2.50 eq.). The milky reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with DCM (75 mL) andwater (75 mL). The mixture was shaken in a separatory funnel and thelayers were separated. The aqueous layer was extracted with DCM (1×25mL), and the combined DCM layers were washed with brine (1×50 mL); dried(Na₂SO₄); filtered; and concentrated. Purified via flash chromatography(Biotage) on a 55 g KPNH column and eluted the product using 100% DCMisocratic for 2 min then ramped to 10% MeOH/DCM over 20 min at a flowrate of 50 mL/min. The product fractions were concentrated and driedunder high vacuum to yield 50 mg (17%) of the title compound as a paleyellow solid. LCMS: 553 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s,1H), 9.55 (d, J=8.1 Hz, 1H), 8.35-8.06 (m, 4H), 7.49 (d, J=5.2 Hz, 1H),7.36 (d, J=8.1 Hz, 1H), 5.30 (t, J=8.6 Hz, 1H), 4.65 (p, J=6.6 Hz, 1H),2.98 (s, 2H), 2.82 (s, 3H), 1.98 (d, J=12.2 Hz, 3H), 1.82 (p, J=10.3,9.9 Hz, 2H), 1.47 (s, 7H), 1.43 (d, J=6.5 Hz, 6H).

Example 21

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded17 mg (39%) of the title compound. LCMS: 553 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.18 (s, 1H), 9.55 (d, J=8.1 Hz, 1H), 8.35-8.06 (m, 4H),7.49 (d, J=5.2 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 5.30 (t, J=8.6 Hz, 1H),4.65 (p, J=6.6 Hz, 1H), 2.98 (s, 2H), 2.82 (s, 3H), 1.98 (d, J=12.2 Hz,3H), 1.82 (p, J=10.3, 9.9 Hz, 2H), 1.47 (s, 7H), 1.43 (d, J=6.5 Hz, 6H).

Example 22

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(S)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded16 mg (36%) of the title compound. LCMS: 553 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.18 (s, 1H), 9.55 (d, J=8.1 Hz, 1H), 8.35-8.06 (m, 4H),7.49 (d, J=5.2 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 5.30 (t, J=8.6 Hz, 1H),4.65 (p, J=6.6 Hz, 1H), 2.98 (s, 2H), 2.82 (s, 3H), 1.98 (d, J=12.2 Hz,3H), 1.82 (p, J=10.3, 9.9 Hz, 2H), 1.47 (s, 7H), 1.43 (d, J=6.5 Hz, 6H).

Example 23

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.In a reaction vial with magnetic stirbar a stirring solution of2-[2-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (364.00 mg; 0.71 mmol; 1.00 eq.),5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid (240.07 mg;1.43 mmol; 2.00 eq.), DIPEA (621.71 μl; 3.57 mmol; 5.00 eq.), DCM (7.28ml; 20.00 V), and DMF (0.75 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (1.06ml; 1.78 mmol; 2.50 eq.). The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted with DCM (50 mL) andwashed with water (1×50 mL) and brine (1×25 mL). The organic layer wasthen dried (Na₂SO₄); filtered; and concentrated. Dissolved in DMSO (2mL) and purified via prep HPLC (Interchim P4250; 30×150 mm C-18 column;0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient 30-80% Bover 20 min. The product fractions were combined and lyophilizedovernight to provide 110 mg (28%) of the title compound as a whitesolid. LCMS: 551 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.49(d, J=8.1 Hz, 1H), 8.26 (d, J=7.0 Hz, 2H), 8.17 (s, 2H), 7.55-7.42 (m,1H), 7.34 (d, J=8.1 Hz, 1H), 5.29 (t, J=8.8 Hz, 1H), 4.65 (p, J=6.6 Hz,1H), 2.98 (d, J=8.6 Hz, 2H), 2.81 (s, 3H), 1.96 (d, J=11.4 Hz, 3H), 1.81(p, J=11.5, 10.6 Hz, 2H), 1.58 (s, 3H), 1.42 (d, J=6.5 Hz, 9H), 1.19 (q,J=4.3 Hz, 2H).

Example 24

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide:The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded36 mg (36%) of the title compound. LCMS: 551 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.19 (s, 1H), 9.49 (d, J=8.1 Hz, 1H), 8.26 (d, J=7.0 Hz,2H), 8.17 (s, 2H), 7.55-7.42 (m, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.29 (t,J=8.8 Hz, 1H), 4.65 (p, J=6.6 Hz, 1H), 2.98 (d, J=8.6 Hz, 2H), 2.81 (s,3H), 1.96 (d, J=11.4 Hz, 3H), 1.81 (p, J=11.5, 10.6 Hz, 2H), 1.58 (s,3H), 1.42 (d, J=6.5 Hz, 9H), 1.19 (q, J=4.3 Hz, 2H).

Example 25

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{(S)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded32 mg (32%) of the title compound. LCMS: 551 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.19 (s, 1H), 9.49 (d, J=8.1 Hz, 1H), 8.26 (d, J=7.0 Hz,2H), 8.17 (s, 2H), 7.55-7.42 (m, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.29 (t,J=8.8 Hz, 1H), 4.65 (p, J=6.6 Hz, 1H), 2.98 (d, J=8.6 Hz, 2H), 2.81 (s,3H), 1.96 (d, J=11.4 Hz, 3H), 1.81 (p, J=11.5, 10.6 Hz, 2H), 1.58 (s,3H), 1.42 (d, J=6.5 Hz, 9H), 1.19 (q, J=4.3 Hz, 2H).

Example 26

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid{2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.In a round bottom flask with magnetic stirbar a stirring solution of2-[2-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (330.00 mg; 0.65 mmol; 1.00 eq.),3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid (870.59 mg;5.18 mmol; 8.00 eq.), DIPEA (563.64 μl; 3.24 mmol; 5.00 eq.), DCM (25.00ml; 75.76 V), and DMF (3.00 ml; 9.09 V) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.96ml; 1.62 mmol; 2.50 eq.) dropwise via syringe over 5 min. The reactionmixture was stirred at room temperature overnight. The reaction wasdiluted with DCM (50 mL) and washed with water (1×50 mL) and brine (1×25mL). The organic layer was then dried (Na₂SO₄); filtered; andconcentrated. Dissolved in DMSO (3 mL); filtered through a syringefilter; and purified via prep HPLC (Interchim P4250; 30×250 mm C-18column; 0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient30-80% B over 20 min. The product fractions were combined andlyophilized overnight to yield 225 mg (63%) of the title compound as awhite solid. LCMS: 551 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H),9.89 (d, J=8.0 Hz, 1H), 8.26 (dd, J=6.4, 3.5 Hz, 2H), 8.15 (d, J=7.3 Hz,2H), 7.49 (d, J=5.2 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.27 (t, J=8.5 Hz,1H), 4.65 (p, J=6.6 Hz, 1H), 2.98 (d, J=6.7 Hz, 2H), 2.82 (s, 3H), 1.97(s, 3H), 1.81 (d, J=11.8 Hz, 2H), 1.52 (s, 3H), 1.42 (d, J=6.5 Hz, 6H),1.38 (d, J=11.2 Hz, 1H), 1.25 (dt, J=4.2, 2.0 Hz, 2H), 1.06-0.98 (m,2H).

Example 27

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid{(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded96 mg (44%) of the title compound. LCMS: 551 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.18 (s, 1H), 9.89 (d, J=8.0 Hz, 1H), 8.26 (dd, J=6.4, 3.5Hz, 2H), 8.15 (d, J=7.3 Hz, 2H), 7.49 (d, J=5.2 Hz, 1H), 7.35 (d, J=8.1Hz, 1H), 5.27 (t, J=8.5 Hz, 1H), 4.65 (p, J=6.6 Hz, 1H), 2.98 (d, J=6.7Hz, 2H), 2.82 (s, 3H), 1.97 (s, 3H), 1.81 (d, J=11.8 Hz, 2H), 1.52 (s,3H), 1.42 (d, J=6.5 Hz, 6H), 1.38 (d, J=11.2 Hz, 1H), 1.25 (dt, J=4.2,2.0 Hz, 2H), 1.06-0.98 (m, 2H).

Example 28

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid{(S)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded100 mg (46%) of the title compound. LCMS: 551 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.18 (s, 1H), 9.89 (d, J=8.0 Hz, 1H), 8.26 (dd, J=6.4, 3.5Hz, 2H), 8.15 (d, J=7.3 Hz, 2H), 7.49 (d, J=5.2 Hz, 1H), 7.35 (d, J=8.1Hz, 1H), 5.27 (t, J=8.5 Hz, 1H), 4.65 (p, J=6.6 Hz, 1H), 2.98 (d, J=6.7Hz, 2H), 2.82 (s, 3H), 1.97 (s, 3H), 1.81 (d, J=11.8 Hz, 2H), 1.52 (s,3H), 1.42 (d, J=6.5 Hz, 6H), 1.38 (d, J=11.2 Hz, 1H), 1.25 (dt, J=4.2,2.0 Hz, 2H), 1.06-0.98 (m, 2H).

Example 29

7-Bromo-2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine(Step 1) To a 50 mL RBF with stirbar was added a mixture of2,3-diamino-4-bromopyridine (2850.00 mg; 15.16 mmol; 1.00 eq.),1-isopropyl-3,5-dimethyl-1h-pyrazole-4-carboxylic acid (3038.21 mg;16.67 mmol; 1.10 eq.) and polyphosphoric acid (13.59 ml). The reactionmixture was heated at 130° C. overnight. Ice was added into the vialwith stirring until a clear brown solution was obtained. The solutionwas transferred to a 1000 mL flask and diluted to 500 mL with water.NaOH (27.2 g; 682.09 mmol; 45.00 eq.) was added to neutralize thereaction mixture to pH 8. The sodium hydroxide was added portion wise sothat the temperature of the aqueous solution did not exceed 50° C. Theproduct precipitated at pH=7-8 (litmus paper). The precipitate wascollected by filtration, washing with H₂O (3×50 mL), and dried undervacuum. Loaded compound onto celite and purified by Biotagechromatography (100 g KP-NH; 75 mL/min; 50-100% EtOAc/hex 15 col. vol.).Concentrated clean product fractions and dried overnight to afford 2.67g (48%) of the title compound as a tan solid. LCMS: 334 (M+H).

{2-[2-(1-Isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-carbamicacid tert-butyl ester (Step 2) In a microwave vial with a stirbar wasadded7-Bromo-2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine(750.00 mg; 2.24 mmol; 1.00 eq.),[2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl]-carbamicacid tert-butyl ester (956.09 mg; 2.47 mmol; 1.10 eq.), Sodium carbonate(713.53 mg; 6.73 mmol; 3.00 eq.), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complexwith dichloromethane (274.89 mg; 0.34 mmol; 0.15 eq.). The vial wassealed then evacuated/N₂-backfilled (3×). EtOH (11.25 ml; 15.00 V) andwater (1.13 ml; 1.50 V) were added via syringe and the vial wasevacuated/N₂-backfilled (3×) again. The mixture was stirred in a 80° C.heating block overnight. The reaction was diluted with EA (15 mL);filtered through a celite plug; and concentrated. Purified via flashchromatography (Biotage): 50 g SiO2 column using 20% EA/Hex isocraticfor 3 min then ramped to 70% EA over 10 min at 100 mL/min. The productfractions were combined, concentrated, and dried under high vacuum toafford 793 mg (69%) of the title compound as a peach solid foam. LCMS:515 (M+H).

2-[2-(1-Isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (Step 3) In a round bottom flask with magnetic stirbar{2-[2-(1-Isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-carbamicacid tert-butyl ester (793.00 mg; 1.39 mmol; 1.00 eq.) was dissolved inmethanol, anhydrous (11.90 ml; 15.00 V). 2.0M hydrogen chloride indiethyl ether (6.93 ml; 13.87 mmol; 10.00 eq.) was then added to thestirring solution. The reaction was stirred at room temperatureovernight. The reaction was diluted with Et2O (50 mL) and the resultingwhite suspension was stirred for 30 min. The solids were filtered anddried under high vacuum to afford 726 mg (99.9%) of the title compoundas an off-white solid. LCMS: 415 (M+H).

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide(Step 4): In a reaction vial with magnetic stirbar a stirring solutionof2-[2-(1-Isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (364.00 mg; 0.69 mmol; 1.00 eq.),5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid (236.45 mg; 1.39 mmol;2.00 eq.), DIPEA (605.07 μl; 3.47 mmol; 5.00 eq.), DCM (7.28 ml; 20.00V), and DMF (0.75 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (1.03ml; 1.74 mmol; 2.50 eq.). The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted with DCM (25 mL) andwashed with water (1×25 mL) and brine (1×25 mL). The organic layer wasthen dried (Na₂SO₄); filtered; and concentrated. Dissolved in DMSO (3mL) and purified via prep HPLC: Interchim P4250; 30×150 mm C-18 column;0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient 30-80% Bover 15 min. The product fractions were combined and lyophilizedovernight to afford 275 mg (70%) of the title compound as a white solid.LCMS: 567 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.55 (d,J=8.1 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.24 (d, J=1.9 Hz, 1H), 8.16 (dd,J=8.0, 1.9 Hz, 1H), 7.52 (d, J=5.2 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.29(t, J=8.6 Hz, 1H), 4.57 (hept, J=6.5 Hz, 1H), 2.98 (d, J=8.5 Hz, 2H),2.56 (s, 3H), 2.43 (s, 3H), 1.97 (d, J=12.7 Hz, 3H), 1.83 (q, J=9.6 Hz,2H), 1.46 (s, 9H), 1.40 (d, J=6.5 Hz, 7H).

Example 30

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(R)-2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded105 mg (40%) of the title compound. LCMS: 567 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 12.75 (s, 1H), 9.55 (d, J=8.1 Hz, 1H), 8.29 (d, J=5.2 Hz,1H), 8.24 (d, J=1.9 Hz, 1H), 8.16 (dd, J=8.0, 1.9 Hz, 1H), 7.52 (d,J=5.2 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.29 (t, J=8.6 Hz, 1H), 4.57(hept, J=6.5 Hz, 1H), 2.98 (d, J=8.5 Hz, 2H), 2.56 (s, 3H), 2.43 (s,3H), 1.97 (d, J=12.7 Hz, 3H), 1.83 (q, J=9.6 Hz, 2H), 1.46 (s, 9H), 1.40(d, J=6.5 Hz, 7H).

Example 31

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(S)-2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded110 mg (42%) of the title compound. LCMS: 567 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 12.75 (s, 1H), 9.55 (d, J=8.1 Hz, 1H), 8.29 (d, J=5.2 Hz,1H), 8.24 (d, J=1.9 Hz, 1H), 8.16 (dd, J=8.0, 1.9 Hz, 1H), 7.52 (d,J=5.2 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.29 (t, J=8.6 Hz, 1H), 4.57(hept, J=6.5 Hz, 1H), 2.98 (d, J=8.5 Hz, 2H), 2.56 (s, 3H), 2.43 (s,3H), 1.97 (d, J=12.7 Hz, 3H), 1.83 (q, J=9.6 Hz, 2H), 1.46 (s, 9H), 1.40(d, J=6.5 Hz, 7H).

Example 32

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.In a reaction vial with magnetic stirbar a stirring solution of2-[2-(1-Isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (364.00 mg; 0.69 mmol; 1.00 eq.),5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid (233.65 mg;1.39 mmol; 2.00 eq.), DIPEA (605.07 μl; 3.47 mmol; 5.00 eq.), DCM (7.28ml; 20.00 V), and DMF (0.75 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (1.03ml; 1.74 mmol; 2.50 eq.). The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted with DCM (25 mL) andwashed with water (1×25 mL) and brine (1×25 mL). The organic layer wasthen dried (Na₂SO₄); filtered; and concentrated. Dissolved in DMSO (3mL) and purified via prep HPLC: Interchim P4250; 30×150 mm C-18 column;0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient 35-80% Bover 15 min. The product fractions were combined and lyophilizedovernight to provide 245 mg (63%) of the title compound as a whitesolid. LCMS: 565 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 9.49(d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.33 (d, J=8.1 Hz, 1H), 5.28 (t, J=8.7Hz, 1H), 4.58 (h, J=6.5 Hz, 1H), 2.97 (d, J=8.0 Hz, 2H), 2.55 (s, 3H),2.42 (s, 3H), 1.96 (d, J=11.4 Hz, 3H), 1.77 (d, J=9.4 Hz, 2H), 1.57 (s,3H), 1.46-1.30 (m, 9H), 1.22-1.14 (m, 2H).

Example 33

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{(R)-2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded93 mg (40%) of the title compound. LCMS: 565 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 12.73 (s, 1H), 9.49 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.33 (d,J=8.1 Hz, 1H), 5.28 (t, J=8.7 Hz, 1H), 4.58 (h, J=6.5 Hz, 1H), 2.97 (d,J=8.0 Hz, 2H), 2.55 (s, 3H), 2.42 (s, 3H), 1.96 (d, J=11.4 Hz, 3H), 1.77(d, J=9.4 Hz, 2H), 1.57 (s, 3H), 1.46-1.30 (m, 9H), 1.22-1.14 (m, 2H).

Example 34

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{(S)-2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded63 mg (27%) of the title compound. LCMS: 565 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 12.73 (s, 1H), 9.49 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.33 (d,J=8.1 Hz, 1H), 5.28 (t, J=8.7 Hz, 1H), 4.58 (h, J=6.5 Hz, 1H), 2.97 (d,J=8.0 Hz, 2H), 2.55 (s, 3H), 2.42 (s, 3H), 1.96 (d, J=11.4 Hz, 3H), 1.77(d, J=9.4 Hz, 2H), 1.57 (s, 3H), 1.46-1.30 (m, 9H), 1.22-1.14 (m, 2H).

Example 35

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid{2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.2-[2-(1-Isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (300.00 mg; 0.57 mmol; 1.00 eq.) was added to areaction vial with EtOH (4.00 mL) and TEA (399.05 μl; 2.86 mmol; 5.00eq.). To the stirring solution was then added3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester(337.04 mg; 1.72 mmol; 3.00 eq.) dissolved in EtOH (0.5 mL). Thereaction was placed under N₂ atmosphere and then the reaction wasstirred in a preheated 75° C. heating block overnight. The reaction wasconcentrated and purified via flash chromatography (Biotage): 55 g KPNHcolumn using 50-100% EA/Hex over 5 min then isocratic 100% EA at a flowrate of 50 mL/min. The product fractions were combined, concentrated,and placed under high vacuum overnight to provide 179 mg (55%) of thetitle compound as an off-white foam solid. LCMS: 565 (M+H). ¹H NMR (400MHz, DMSO-d6) δ 12.75 (s, 1H), 9.89 (d, J=8.0 Hz, 1H), 8.29 (d, J=5.2Hz, 1H), 8.23 (d, J=1.9 Hz, 1H), 8.16 (dd, J=8.1, 1.9 Hz, 1H), 7.51 (d,J=5.3 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.26 (t, J=8.5 Hz, 1H), 4.57 (p,J=6.5 Hz, 1H), 2.97 (d, J=8.0 Hz, 2H), 2.56 (s, 3H), 2.43 (s, 3H),2.03-1.89 (m, 3H), 1.81 (d, J=11.7 Hz, 2H), 1.52 (s, 3H), 1.40 (d, J=6.5Hz, 7H), 1.25 (dt, J=4.1, 1.8 Hz, 2H), 1.04-0.98 (m, 2H).

Example 36

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid{(S)-2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded60 mg (35%) of the title compound. LCMS: 565 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 12.75 (s, 1H), 9.89 (d, J=8.0 Hz, 1H), 8.29 (d, J=5.2 Hz,1H), 8.23 (d, J=1.9 Hz, 1H), 8.16 (dd, J=8.1, 1.9 Hz, 1H), 7.51 (d,J=5.3 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.26 (t, J=8.5 Hz, 1H), 4.57 (p,J=6.5 Hz, 1H), 2.97 (d, J=8.0 Hz, 2H), 2.56 (s, 3H), 2.43 (s, 3H),2.03-1.89 (m, 3H), 1.81 (d, J=11.7 Hz, 2H), 1.52 (s, 3H), 1.40 (d, J=6.5Hz, 7H), 1.25 (dt, J=4.1, 1.8 Hz, 2H), 1.04-0.98 (m, 2H).

Example 37

7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (Step 1)To a 500 mL RBF with stirbar was added a mixture of4-Bromo-pyridine-2,3-diamine (35.00 g; 186.15 mmol; 1.00 eq.),1-methyl-1h-pyrazole-4-carboxylic acid (25.82 g; 204.76 mmol; 1.10 eq.)and polyphosphoric acid (160.00 ml). The reaction mixture was heated at130° C. overnight. Ice was added into the vial with stirring until aclear brown solution was obtained. The solution was transferred to a 2 Lflask and then ammonium chloride (19914.21 mg; 372.29 mmol; 2.00 eq.)and NaOH (335036.70 mg; 8376.55 mmol; 45.00 eq.) were added toneutralize reaction mixture to pH 7. Sodium hydroxide was added portionwise so that the temperature of the aqueous solution did not exceed 50°C. (cooling by adding ice pellets from time to time). The productprecipitated at pH=7. The suspension was chilled at 4° C. in fridgeovernight. The precipitate was collected by filtration, washing with H₂O(3×100 mL), and dried under high vacuum to afford 44.5 g (82%) of thetitle compound as a brown solid. LCMS: 278 (M+H).

{8-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-carbamicacid tert-butyl ester (Step 2) In a microwave vial with a stirbar wasadded 7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine(275.00 mg; 0.79 mmol; 1.00 eq.),[8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl]-carbamicacid tert-butyl ester (400.34 mg; 1.03 mmol; 1.30 eq.), Sodium carbonate(251.53 mg; 2.37 mmol; 3.00 eq.), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complexwith dichloromethane (96.90 mg; 0.12 mmol; 0.15 eq.). The vial wassealed then evacuated/N₂-backfilled (3×). EtOH (5.50 ml; 20.00 V) andwater (0.55 ml; 2.00 V) were added via syringe and the vial wasevacuated/N₂-backfilled (3×) again. The mixture was stirred in a 80° C.heating block overnight. The reaction was diluted with DCM (10 mL);filtered through a celite plug; and concentrated on KPNH silica.Purified via flash chromatography (Biotage): 28 g KPNH column using50-100% EA/Hex over 5 min followed by a ramp of 0-10% MeOH/EA was ran toelute the product. The product fractions were combined, concentrated,and placed under high vacuum overnight to afford 330 mg (91%) of thetitle compound as a yellow solid. LCMS: 461 (M+H).

8-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-ylaminehydrochloride (Step 3) In a reaction vial with magnetic stirbar{8-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-carbamicacid tert-butyl ester (330.00 mg; 0.72 mmol; 1.00 eq.) was dissolved inmethanol, anhydrous (5.00 ml; 123.43 mmol; 15.15 V). 4.0M hydrogenchloride in dioxane (5.00 ml; 10.00 mmol; 13.96 eq.) was then added tothe stirring solution. The reaction was stirred at room temperature for30 min. The reaction was concentrated to a dark yellow solid and placedunder high vacuum overnight. LCMS: 361 (M+H).

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide(Step 4) In a reaction vial with magnetic stirbar a stirring solution of8-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-ylaminehydrochloride (3) (169.13 mg; 0.36 mmol; 1.00 eq.),5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid (122.52 mg; 0.72 mmol;2.00 eq.), DIPEA (313.53 μl; 1.80 mmol; 5.00 eq.), DCM (3.38 ml; 20.00V), and DMF (0.96 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.54ml; 0.90 mmol; 2.50 eq.). The reaction mixture (pH 9) was stirred atroom temperature for 90 min. The reaction was diluted with DCM (25 mL)and washed with water (1×20 mL) and brine (1×20 mL). The organic layerwas then dried (Na₂SO₄); filtered; and concentrated. Dissolved in DMSO(3 mL) and purified via prep HPLC (Interchim P4250; 30×150 mm C-18column; 0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient20-80% B over 15 min. The product fractions were combined andlyophilized overnight to afford 140 mg (76%) of the title compound as awhite solid. LCMS: 513 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H),9.40 (d, J=8.4 Hz, 1H), 8.43 (s, 1H), 8.27 (d, J=5.3 Hz, 1H), 8.13 (s,1H), 8.04 (d, J=8.1 Hz, 1H), 7.98 (s, 1H), 7.46 (s, 1H), 7.37 (d, J=8.1Hz, 1H), 5.33 (d, J=7.3 Hz, 1H), 4.31 (d, J=12.0 Hz, 1H), 3.95 (s, 3H),3.90-3.78 (m, 1H), 2.02 (s, 4H), 1.46 (s, 9H).

Example 38

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid{8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.In a reaction vial with magnetic stirbar a stirring solution of8-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-ylaminehydrochloride (3) (169.13 mg; 0.36 mmol; 1.00 eq.),3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid (122.52 mg; 0.72 mmol;2.00 eq.), DIPEA (313.53 μl; 1.80 mmol; 5.00 eq.), DCM (3.38 ml; 20.00V), and DMF (0.96 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.54ml; 0.90 mmol; 2.50 eq.). The reaction mixture (pH 9) was stirred atroom temperature for 90 min. The reaction was diluted with DCM (25 mL)and washed with water (1×20 mL) and brine (1×20 mL). The organic layerwas then dried (Na₂SO₄); filtered; and concentrated. Dissolved in DMSO(3 mL) and purified via prep HPLC (Interchim P4250; 30×150 mm C-18column; 0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient 20mg −80% B over 15 min. The product fractions were combined andlyophilized overnight to afford 100 (54%) of the title compound as awhite solid. LCMS: 513 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H),9.85 (d, J=8.3 Hz, 1H), 8.42 (s, 1H), 8.27 (d, J=5.2 Hz, 1H), 8.12 (s,1H), 8.04 (d, J=8.1 Hz, 1H), 7.98 (s, 1H), 7.47 (d, J=5.2 Hz, 1H), 7.39(d, J=8.1 Hz, 1H), 5.31 (d, J=7.9 Hz, 1H), 4.34 (d, J=12.0 Hz, 1H), 3.95(s, 3H), 3.83 (d, J=11.5 Hz, 1H), 2.04 (s, 4H), 1.40 (s, 9H).

Example 39

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.In a reaction vial with magnetic stirbar was added2-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (168.00 mg; 0.36 mmol; 1.00 eq.),5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid (122.22 mg; 0.72 mmol;2.00 eq.), DCM (3.36 ml; 20.00 V), DMF (0.96 ml) and DIPEA (625.51 μl;3.59 mmol; 10.00 eq.). After ˜10 min the solids had not completelydissolved, additional DMF (3 mL) was added. The suspension was thentreated with 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane2,4,6-trioxide (0.53 ml; 0.90 mmol; 2.50 eq.). The reaction mixture (pH10) was stirred at room temperature for 90 min. The reaction was dilutedwith DCM (25 mL) and washed with water (1×20 mL) and brine (1×20 mL).The organic layer was then dried (Na₂SO₄); filtered; and concentrated.Dissolved in DMSO (3 mL) and purified via prep HPLC (Interchim P4250);30×150 mm C-18 column; 0.1% NH₄OH modified mobile phases (A=water,B=ACN); gradient 30-80% B over 18 min. The product fractions werecombined and lyophilized overnight to afford 110 mg (59%) of the titlecompound a white solid. LCMS: 511 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ13.29 (s, 1H), 9.56 (d, J=7.9 Hz, 1H), 8.43 (s, 1H), 8.27 (d, J=4.7 Hz,1H), 8.16 (d, J=15.6 Hz, 2H), 8.06 (s, 1H), 7.46 (s, 1H), 7.36 (d, J=8.0Hz, 1H), 5.30 (t, J=8.7 Hz, 1H), 3.95 (s, 3H), 2.99 (d, J=6.6 Hz, 2H),1.99 (d, J=14.4 Hz, 3H), 1.84 (q, J=10.2 Hz, 2H), 1.47 (s, 9H), 1.40 (d,J=15.4 Hz, 1H).

Example 40

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.In a reaction vial with magnetic stirbar a stirring solution of2-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (168.00 mg; 0.36 mmol; 1.00 eq.),5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid (120.77 mg;0.72 mmol; 2.00 eq.), DIPEA (625.51 μl; 3.59 mmol; 10.00 eq.), and DMF(4.00 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.53ml; 0.90 mmol; 2.50 eq.). The reaction mixture (pH 10) was stirred atroom temperature for 1 hr. The reaction was diluted with DCM (25 mL) andwashed with water (1×20 mL) and brine (1×20 mL). The organic layer wasthen dried (Na₂SO₄); filtered; and concentrated. Dissolved in DMSO (3mL) and purified via prep HPLC (Interchim P4250); 30×150 mm C-18 column;0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient 30-80% Bover 18 min. The product fractions were combined and lyophilizedovernight to afford 96 mg (51%) of the title compound as a white solid.LCMS: 509 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 9.49 (d,J=8.0 Hz, 1H), 8.43 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.21-8.15 (m, 1H),8.13 (s, 1H), 8.06 (s, 1H), 7.47 (d, J=5.2 Hz, 1H), 7.34 (d, J=8.1 Hz,1H), 5.28 (t, J=8.7 Hz, 1H), 3.95 (s, 3H), 2.99 (d, J=6.9 Hz, 2H), 1.97(s, 3H), 1.90-1.74 (m, 2H), 1.58 (s, 3H), 1.43 (q, J=4.0 Hz, 2H), 1.38(s, 1H), 1.23-1.16 (m, 2H).

Example 41

5-(1-Methyl-cyclopropyl)-isoxazole-3-carboxylic acid{2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.In a reaction vial with magnetic stirbar a stirring solution of2-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (168.00 mg; 0.36 mmol; 1.00 eq.),5-(1-Methyl-cyclopropyl)-isoxazole-3-carboxylic acid (120.06 mg; 0.72mmol; 2.00 eq.), DIPEA (625.51 μl; 3.59 mmol; 10.00 eq.), and DMF (4.00ml) was treated with 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane2,4,6-trioxide (0.53 ml; 0.90 mmol; 2.50 eq.). The reaction mixture (pH10) was stirred at room temperature for 1 hr. The reaction was dilutedwith DCM (25 mL) and washed with water (1×20 mL) and brine (1×20 mL).The organic layer was then dried (Na₂SO₄); filtered; and concentrated.Dissolved in DMSO (3 mL) and purified via prep HPLC (Interchim P4250);30×150 mm C-18 column; 0.1% NH₄OH modified mobile phases (A=water,B=ACN); gradient 30-80% B over 18 min. The product fractions werecombined and lyophilized overnight to afford 145 mg (80%) of the titlecompound as a white solid. LCMS: 508 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ13.29 (s, 1H), 9.27 (d, J=8.1 Hz, 1H), 8.42 (s, 1H), 8.26 (d, J=5.2 Hz,1H), 8.21-8.15 (m, 1H), 8.13 (s, 1H), 8.09-8.01 (m, 1H), 7.47 (d, J=5.2Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.63 (s, 1H), 5.27 (t, J=8.9 Hz, 1H),3.95 (s, 3H), 2.98 (d, J=6.7 Hz, 2H), 1.96 (d, J=10.1 Hz, 3H), 1.81 (dt,J=20.6, 10.9 Hz, 2H), 1.48 (s, 3H), 1.34 (d, J=17.8 Hz, 1H), 1.19 (q,J=4.1 Hz, 2H), 1.02-0.95 (m, 2H).

Example 42

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid{2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.In a reaction vial with magnetic stirbar a stirring solution of2-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (168.00 mg; 0.36 mmol; 1.00 eq.),5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid (122.22 mg; 0.72 mmol;2.00 eq.), DIPEA (625.51 μl; 3.59 mmol; 10.00 eq.), and DMF (4.00 ml)was treated with 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane2,4,6-trioxide (0.53 ml; 0.90 mmol; 2.50 eq.). The reaction mixture (pH10) was stirred at room temperature for 1 hr. The reaction was dilutedwith DCM (25 mL) and washed with water (1×20 mL) and brine (1×20 mL).The organic layer was then dried (Na₂SO₄); filtered; and concentrated.Dissolved in DMSO (3 mL) and purified via prep HPLC (Interchim P4250);30×150 mm C-18 column; 0.1% NH₄OH modified mobile phases (A=water,B=ACN); gradient 30-80% B over 18 min. The product fractions werecombined and lyophilized overnight to afford 130 mg (70%) of the titlecompound as a white solid. LCMS: 511 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ13.30 (s, 1H), 9.89 (d, J=8.0 Hz, 1H), 8.42 (s, 1H), 8.26 (d, J=5.2 Hz,1H), 8.23-8.15 (m, 1H), 8.13 (s, 1H), 8.09-8.03 (m, 1H), 7.47 (d, J=5.2Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 5.28 (t, J=8.5 Hz, 1H), 3.94 (s, 3H),2.99 (d, J=7.6 Hz, 2H), 1.98 (s, 3H), 1.92-1.76 (m, 2H), 1.44 (s, 9H),1.37 (s, 1H).

Example 43

3-tert-Butoxy-azetidine-1-carboxylic acid{2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.In a reaction vial with magnetic stirbar2-[2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (190.00 mg; 0.41 mmol; 1.00 eq.) was added followed byDMF (4.00 ml; 51.88 mmol; 21.05 V) and Ethyl-diisopropyl-amine (403.77μl; 2.44 mmol; 6.00 eq.). To the stirring solution was then addedDi-imidazol-1-yl-methanone (98.78 mg; 0.61 mmol; 1.50 eq.). Afterstirring for 2 h at room temperature, 3-tert-Butoxy-azetidinehydrochloride (80.74 mg; 0.49 mmol; 1.20 eq.) was added and the reactionwas stirred overnight. The reaction was partially concentrated and thenpurified directly via prep HPLC (Interchim P4250); 30×150 mm C-18column; 0.1% formic acid modified mobile phases (A=water, B=ACN);gradient 20-75% B over 20 min at 60 mL/min). The product fractions werecombined and lyophilized overnight to afford 142 mg (67%) of the titlecompound as a white solid. LCMS: 514 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ13.17 (s, 1H), 8.43 (s, 1H), 8.26 (d, J=5.0 Hz, 1H), 8.14 (s, 2H), 8.00(s, 1H), 7.44 (s, 1H), 7.36 (d, J=8.1 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H),4.91 (t, J=9.1 Hz, 1H), 4.50 (ddd, J=11.6, 6.6, 5.0 Hz, 1H), 4.17-4.04(m, 2H), 3.95 (s, 3H), 3.66 (ddd, J=17.3, 8.6, 5.0 Hz, 2H), 2.92 (d,J=11.2 Hz, 2H), 1.91 (s, 3H), 1.79 (q, J=11.7, 9.2 Hz, 1H), 1.70-1.55(m, 1H), 1.43-1.26 (m, 1H), 1.15 (s, 9H).

Example 44

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid{(R)-8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded28 mg (30%) of the title compound. LCMS: 513 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 9.84 (d, J=7.9 Hz, 1H), 8.39 (s, 1H), 8.24 (d, J=5.1 Hz, 1H),8.10 (s, 1H), 7.98 (d, J=23.8 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 5.31 (s,1H), 4.33 (d, J=12.0 Hz, 1H), 3.94 (s, 3H), 3.83 (d, J=10.7 Hz, 1H),2.04 (s, 4H), 1.40 (s, 9H).

Example 45

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid{(S)-8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded29 mg (31%) of the title compound. LCMS: 513 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 9.84 (d, J=7.9 Hz, 1H), 8.39 (s, 1H), 8.24 (d, J=5.1 Hz, 1H),8.10 (s, 1H), 7.98 (d, J=23.8 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 5.31 (s,1H), 4.33 (d, J=12.0 Hz, 1H), 3.94 (s, 3H), 3.83 (d, J=10.7 Hz, 1H),2.04 (s, 4H), 1.40 (s, 9H).

Example 46

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(R)-8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded36 mg (27%) of the title compound. LCMS: 513 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 9.40 (d, J=8.4 Hz, 1H), 8.41 (s, 1H), 8.25 (d, J=5.2 Hz, 1H),8.12 (d, J=0.7 Hz, 1H), 7.98 (d, J=23.1 Hz, 2H), 7.42 (s, 1H), 7.37 (d,J=8.1 Hz, 1H), 5.33 (q, J=6.7, 6.3 Hz, 1H), 4.31 (d, J=12.0 Hz, 1H),3.94 (s, 3H), 3.84 (dd, J=11.9, 7.9 Hz, 1H), 2.02 (s, 4H), 1.46 (s, 9H).

Example 47

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(S)-8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded33 mg (25%) of the title compound. LCMS: 513 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 9.40 (d, J=8.4 Hz, 1H), 8.41 (s, 1H), 8.25 (d, J=5.2 Hz, 1H),8.12 (d, J=0.7 Hz, 1H), 7.98 (d, J=23.1 Hz, 2H), 7.42 (s, 1H), 7.37 (d,J=8.1 Hz, 1H), 5.33 (q, J=6.7, 6.3 Hz, 1H), 4.31 (d, J=12.0 Hz, 1H),3.94 (s, 3H), 3.84 (dd, J=11.9, 7.9 Hz, 1H), 2.02 (s, 4H), 1.46 (s, 9H).

Example 48

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid{(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded36 mg (30%) of the title compound. LCMS: 511 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.29 (s, 1H), 9.88 (d, J=8.0 Hz, 1H), 8.42 (s, 1H), 8.26 (d,J=5.2 Hz, 1H), 8.18 (dd, J=8.1, 1.8 Hz, 1H), 8.13 (s, 1H), 8.06 (d,J=1.9 Hz, 1H), 7.46 (d, J=5.2 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 5.28 (t,J=8.5 Hz, 1H), 3.94 (s, 3H), 2.99 (t, J=5.2 Hz, 2H), 1.98 (s, 3H), 1.84(t, J=9.6 Hz, 2H), 1.43 (s, 9H), 1.38 (d, J=5.6 Hz, 1H).

Example 49

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid{(S)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded42 mg (34%) of the title compound. LCMS: 511 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.29 (s, 1H), 9.88 (d, J=8.0 Hz, 1H), 8.42 (s, 1H), 8.26 (d,J=5.2 Hz, 1H), 8.18 (dd, J=8.1, 1.8 Hz, 1H), 8.13 (s, 1H), 8.06 (d,J=1.9 Hz, 1H), 7.46 (d, J=5.2 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 5.28 (t,J=8.5 Hz, 1H), 3.94 (s, 3H), 2.99 (t, J=5.2 Hz, 2H), 1.98 (s, 3H), 1.84(t, J=9.6 Hz, 2H), 1.43 (s, 9H), 1.38 (d, J=5.6 Hz, 1H).

Example 50

3-tert-Butoxy-azetidine-1-carboxylic acid{(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded44 mg (33%) of the title compound. LCMS: 514 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 8.42 (s, 1H), 8.25 (d, J=5.1 Hz, 1H), 8.04 (d, J=74.9 Hz,3H), 7.38 (dd, J=13.9, 6.5 Hz, 2H), 6.83 (d, J=8.1 Hz, 1H), 4.91 (t,J=9.2 Hz, 1H), 4.50 (p, J=5.9 Hz, 1H), 4.10 (dt, J=16.4, 7.7 Hz, 2H),3.95 (s, 3H), 3.66 (ddd, J=17.0, 8.6, 5.1 Hz, 2H), 2.92 (d, J=11.2 Hz,2H), 1.92 (d, J=10.3 Hz, 3H), 1.78 (d, J=10.5 Hz, 1H), 1.62 (d, J=11.0Hz, 1H), 1.33 (d, J=13.7 Hz, 1H), 1.15 (s, 9H).

Example 51

3-tert-Butoxy-azetidine-1-carboxylic acid{(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded44 mg (33%) of the title compound. LCMS: 514 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 8.42 (s, 1H), 8.25 (d, J=5.1 Hz, 1H), 8.04 (d, J=74.9 Hz,3H), 7.38 (dd, J=13.9, 6.5 Hz, 2H), 6.83 (d, J=8.1 Hz, 1H), 4.91 (t,J=9.2 Hz, 1H), 4.50 (p, J=5.9 Hz, 1H), 4.10 (dt, J=16.4, 7.7 Hz, 2H),3.95 (s, 3H), 3.66 (ddd, J=17.0, 8.6, 5.1 Hz, 2H), 2.92 (d, J=11.2 Hz,2H), 1.92 (d, J=10.3 Hz, 3H), 1.78 (d, J=10.5 Hz, 1H), 1.62 (d, J=11.0Hz, 1H), 1.33 (d, J=13.7 Hz, 1H), 1.15 (s, 9H).

Example 52

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded41 mg (40%) of the title compound. LCMS: 511 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.29 (s, 1H), 9.56 (d, J=7.9 Hz, 1H), 8.43 (s, 1H), 8.27 (d,J=4.7 Hz, 1H), 8.16 (d, J=15.6 Hz, 2H), 8.06 (s, 1H), 7.46 (s, 1H), 7.36(d, J=8.0 Hz, 1H), 5.30 (t, J=8.7 Hz, 1H), 3.95 (s, 3H), 2.99 (d, J=6.6Hz, 2H), 1.99 (d, J=14.4 Hz, 3H), 1.84 (q, J=10.2 Hz, 2H), 1.47 (s, 9H),1.40 (d, J=15.4 Hz, 1H).

Example 53

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(S)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amid.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded39 mg (38%) of the title compound. LCMS: 511 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.29 (s, 1H), 9.56 (d, J=7.9 Hz, 1H), 8.43 (s, 1H), 8.27 (d,J=4.7 Hz, 1H), 8.16 (d, J=15.6 Hz, 2H), 8.06 (s, 1H), 7.46 (s, 1H), 7.36(d, J=8.0 Hz, 1H), 5.30 (t, J=8.7 Hz, 1H), 3.95 (s, 3H), 2.99 (d, J=6.6Hz, 2H), 1.99 (d, J=14.4 Hz, 3H), 1.84 (q, J=10.2 Hz, 2H), 1.47 (s, 9H),1.40 (d, J=15.4 Hz, 1H).

Example 54

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded38 mg (41%) of the title compound. LCMS: 509 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.29 (s, 1H), 9.49 (d, J=8.0 Hz, 1H), 8.43 (s, 1H), 8.26 (d,J=5.2 Hz, 1H), 8.21-8.15 (m, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.47 (d,J=5.2 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.28 (t, J=8.7 Hz, 1H), 3.95 (s,3H), 2.99 (d, J=6.9 Hz, 2H), 1.97 (s, 3H), 1.90-1.74 (m, 2H), 1.58 (s,3H), 1.43 (q, J=4.0 Hz, 2H), 1.38 (s, 1H), 1.23-1.16 (m, 2H).

Example 55

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid{(S)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded31 mg (34%) of the title compound. LCMS: 509 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.29 (s, 1H), 9.49 (d, J=8.0 Hz, 1H), 8.43 (s, 1H), 8.26 (d,J=5.2 Hz, 1H), 8.21-8.15 (m, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.47 (d,J=5.2 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.28 (t, J=8.7 Hz, 1H), 3.95 (s,3H), 2.99 (d, J=6.9 Hz, 2H), 1.97 (s, 3H), 1.90-1.74 (m, 2H), 1.58 (s,3H), 1.43 (q, J=4.0 Hz, 2H), 1.38 (s, 1H), 1.23-1.16 (m, 2H).

Example 56

5-(1-Methyl-cyclopropyl)-isoxazole-3-carboxylic acid{(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded59 mg (43%) of the title compound. LCMS: 508 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.29 (s, 1H), 9.27 (d, J=8.1 Hz, 1H), 8.42 (s, 1H), 8.26 (d,J=5.2 Hz, 1H), 8.21-8.15 (m, 1H), 8.13 (s, 1H), 8.09-8.01 (m, 1H), 7.47(d, J=5.2 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.63 (s, 1H), 5.27 (t, J=8.9Hz, 1H), 3.95 (s, 3H), 2.98 (d, J=6.7 Hz, 2H), 1.96 (d, J=10.1 Hz, 3H),1.81 (dt, J=20.6, 10.9 Hz, 2H), 1.48 (s, 3H), 1.34 (d, J=17.8 Hz, 1H),1.19 (q, J=4.1 Hz, 2H), 1.02-0.95 (m, 2H).

Example 57

5-(1-Methyl-cyclopropyl)-isoxazole-3-carboxylic acid{(S)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded59 mg (43%) of the title compound. LCMS: 508 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.29 (s, 1H), 9.27 (d, J=8.1 Hz, 1H), 8.42 (s, 1H), 8.26 (d,J=5.2 Hz, 1H), 8.21-8.15 (m, 1H), 8.13 (s, 1H), 8.09-8.01 (m, 1H), 7.47(d, J=5.2 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.63 (s, 1H), 5.27 (t, J=8.9Hz, 1H), 3.95 (s, 3H), 2.98 (d, J=6.7 Hz, 2H), 1.96 (d, J=10.1 Hz, 3H),1.81 (dt, J=20.6, 10.9 Hz, 2H), 1.48 (s, 3H), 1.34 (d, J=17.8 Hz, 1H),1.19 (q, J=4.1 Hz, 2H), 1.02-0.95 (m, 2H).

Example 58

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.In a reaction vial with magnetic stirbar a stirring solution of2-[2-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylaminehydrochloride (3) (160.00 mg; 0.31 mmol; 1.00 eq.),5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid (106.79 mg; 0.63 mmol;2.00 eq.), DIPEA (273.28 μl; 1.57 mmol; 5.00 eq.), DCM (3.20 ml; 20.00V), and DMF (0.50 ml) was treated with2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (466.98μl; 0.78 mmol; 2.50 eq.). The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted with DCM (50 mL) andwashed with water (1×50 mL) and brine (1×25 mL). The organic layer wasthen dried (Na₂SO₄); filtered; and concentrated. Dissolved in DMSO (2mL) and purified via prep HPLC (Interchim P4250); 30×250 mm C-18 column;0.1% NH₄OH modified mobile phases (A=water, B=ACN); gradient 35-65% Bover 20 min. The product fractions were combined and lyophilized toafford 149 mg (86%) of the title compound as a white solid. LCMS: 553(M+H). ¹H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.55 (d, J=8.0 Hz,1H), 8.39 (s, 1H), 8.30 (d, J=1.9 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.18(dd, J=8.1, 1.9 Hz, 1H), 7.50 (d, J=5.3 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H),5.30 (t, J=8.6 Hz, 1H), 4.51 (p, J=6.6 Hz, 1H), 2.99 (d, J=9.3 Hz, 2H),2.62 (s, 3H), 1.96 (s, 3H), 1.83 (q, J=9.6 Hz, 2H), 1.46 (d, J=3.1 Hz,16H), 1.38 (s, 1H).

Example 59

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid{(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded30 mg (37%) of the title compound. LCMS: 551 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.04 (s, 1H), 9.88 (d, J=7.9 Hz, 1H), 8.39 (s, 1H), 8.29 (d,J=1.9 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.18 (dd, J=8.2, 1.9 Hz, 1H),7.49 (d, J=5.3 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.27 (t, J=8.5 Hz, 1H),4.51 (p, J=6.6 Hz, 1H), 2.98 (d, J=7.8 Hz, 2H), 2.62 (s, 3H), 1.97 (s,3H), 1.81 (d, J=13.5 Hz, 2H), 1.52 (s, 3H), 1.47 (d, J=6.6 Hz, 6H), 1.36(s, 1H), 1.25 (dt, J=4.1, 1.9 Hz, 2H), 1.08-0.96 (m, 2H).

Example 60

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid{(S)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded28 mg (34%) of the title compound. LCMS: 551 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.04 (s, 1H), 9.88 (d, J=7.9 Hz, 1H), 8.39 (s, 1H), 8.29 (d,J=1.9 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.18 (dd, J=8.2, 1.9 Hz, 1H),7.49 (d, J=5.3 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.27 (t, J=8.5 Hz, 1H),4.51 (p, J=6.6 Hz, 1H), 2.98 (d, J=7.8 Hz, 2H), 2.62 (s, 3H), 1.97 (s,3H), 1.81 (d, J=13.5 Hz, 2H), 1.52 (s, 3H), 1.47 (d, J=6.6 Hz, 6H), 1.36(s, 1H), 1.25 (dt, J=4.1, 1.9 Hz, 2H), 1.08-0.96 (m, 2H).

Example 61

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded48 mg (34%) of the title compound. LCMS: 553 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.04 (s, 1H), 9.55 (d, J=8.0 Hz, 1H), 8.39 (s, 1H), 8.30 (d,J=1.9 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.18 (dd, J=8.1, 1.9 Hz, 1H),7.50 (d, J=5.3 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 5.30 (t, J=8.6 Hz, 1H),4.51 (p, J=6.6 Hz, 1H), 2.99 (d, J=9.3 Hz, 2H), 2.62 (s, 3H), 1.96 (s,3H), 1.83 (q, J=9.6 Hz, 2H), 1.46 (d, J=3.1 Hz, 16H), 1.38 (s, 1H).

Example 62

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid{(S)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded50 mg (36%) of the title compound. LCMS: 553 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.04 (s, 1H), 9.55 (d, J=8.0 Hz, 1H), 8.39 (s, 1H), 8.30 (d,J=1.9 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.18 (dd, J=8.1, 1.9 Hz, 1H),7.50 (d, J=5.3 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 5.30 (t, J=8.6 Hz, 1H),4.51 (p, J=6.6 Hz, 1H), 2.99 (d, J=9.3 Hz, 2H), 2.62 (s, 3H), 1.96 (s,3H), 1.83 (q, J=9.6 Hz, 2H), 1.46 (d, J=3.1 Hz, 16H), 1.38 (s, 1H).

Example 63

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid{(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded22 mg (33%) of the title compound. LCMS: 553 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.04 (s, 1H), 9.95 (d, J=8.0 Hz, 1H), 8.39 (s, 1H), 8.30 (d,J=1.9 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.18 (dd, J=8.2, 1.9 Hz, 1H),7.50 (d, J=5.3 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 5.29 (t, J=8.5 Hz, 1H),4.51 (p, J=6.6 Hz, 1H), 2.99 (d, J=8.3 Hz, 2H), 2.62 (s, 3H), 2.00 (d,J=20.4 Hz, 3H), 1.84 (t, J=9.4 Hz, 2H), 1.47 (d, J=6.7 Hz, 6H), 1.41 (s,9H), 1.37 (d, J=9.7 Hz, 1H).

Example 64

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid{(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded21 mg (32%) of the title compound. LCMS: 553 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.04 (s, 1H), 9.95 (d, J=8.0 Hz, 1H), 8.39 (s, 1H), 8.30 (d,J=1.9 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.18 (dd, J=8.2, 1.9 Hz, 1H),7.50 (d, J=5.3 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 5.29 (t, J=8.5 Hz, 1H),4.51 (p, J=6.6 Hz, 1H), 2.99 (d, J=8.3 Hz, 2H), 2.62 (s, 3H), 2.00 (d,J=20.4 Hz, 3H), 1.84 (t, J=9.4 Hz, 2H), 1.47 (d, J=6.7 Hz, 6H), 1.41 (s,9H), 1.37 (d, J=9.7 Hz, 1H).

Example 65

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid{(R)-2-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded6 mg (27%) of the title compound. LCMS: 539 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.32 (s, 1H), 9.97 (d, J=7.6 Hz, 1H), 8.27 (d, J=5.1 Hz,1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.42 (s, 1H), 7.38 (d, J=8.1 Hz, 1H),6.75 (s, 1H), 5.28 (s, 1H), 3.86 (s, 3H), 2.99 (d, J=7.1 Hz, 2H),2.75-2.65 (m, 2H), 2.00 (d, J=22.5 Hz, 3H), 1.85 (t, J=9.5 Hz, 2H), 1.41(s, 9H), 1.27 (t, J=7.5 Hz, 3H).

Example 66

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid{(S)-2-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide.The title compound was obtained via chiral SFC using ChiralPak AD-H21×250 mm and a mobile phase of 30% 2-Propanol+0.5% DMEA in CO₂. Yielded6 mg (27%) of the title compound. LCMS: 539 (M+H). ¹H NMR (400 MHz,DMSO-d6) δ 13.32 (s, 1H), 9.97 (d, J=7.6 Hz, 1H), 8.27 (d, J=5.1 Hz,1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.42 (s, 1H), 7.38 (d, J=8.1 Hz, 1H),6.75 (s, 1H), 5.28 (s, 1H), 3.86 (s, 3H), 2.99 (d, J=7.1 Hz, 2H),2.75-2.65 (m, 2H), 2.00 (d, J=22.5 Hz, 3H), 1.85 (t, J=9.5 Hz, 2H), 1.41(s, 9H), 1.27 (t, J=7.5 Hz, 3H).

Methods for IAP Fused Analogs in Exemplification Table 1.

Method A:

Method B:

Method C:

Method D

Example Table 1

Example # and Preparation IUPAC Name Structure Method Starting MaterialExample 67  3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {6-[2-(1,3-dimethyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 7-Bromo-2-(1,3- dimethyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridine LCMS: 511 (M + H). ¹H NMR (400 MHz, DMSO-d₆) d 13.13 (s, 1H),9.75 (d, J = 8.7 Hz, 1H), 8.42-8.21 (m, 3H), 8.15 (dd, J = 8.2, 1.9 Hz,1H), 7.60-7.30 (m, 2H), 5.28 (d, J = 4.9 Hz, 1H), 3.88 (s, 3H), 2.89 (d,J = 6.3 Hz, 2H), 2.61 (s, 3H), 2.20-1.71 (m, 4H), 1.37 (s, 9H). Example68  3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {6-[2-(1,3,5-trimethyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 7-Bromo-2-(1,3,5- trimethyl-1H-pyrazol- 4-yl)-3H-imidazo[4,5-b]pyridine LCMS: 525 (M + H). ¹H NMR (400 MHz, DMSO-d₆) 12.76 (s, 1H),9.76 (d, J = 8.7 Hz, 1H), 8.52-8.22 (m, 2H), 8.22-8.03 (m, 1H), 7.51 (d,J = 5.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 5.44-5.14 (m, 1H), 3.76 (s,3H), 2.89 (s, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 2.13-1.68 (m, 3H), 1.37(s, 9H). Example 69  3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{1-[4- (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-phenyl]-cyclopropyl]-amide

Method A 2-[2-(1,3,5-Trimethyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine LCMS: 524 (M + H). 1H NMR (400 MHz, DMSO-d6) d 9.29 (d, J = 8.2Hz, 1H), 8.20 (d, J = 43.1 Hz, 3H), 7.34 (d, J = 8.1 Hz, 1H), 6.64 (d, J= 0.9 Hz, 1H), 5.28 (t, J = 8.6 Hz, 1H), 3.75 (s, 3H), 3.21-3.09 (m,1H), 2.56 (s, 3H), 2.43 (s, 3H), 1.89 (dd, J = 62.3, 13.7 Hz, 4H), 1.30(d, J = 6.9 Hz, 6H). Example 70  5-tert-butyl-N-12-[2-(1,3,5-trimethyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl}-1,2-oxazole-3- carboxamide

Method B 2-[2-(1,3,5-Trimethyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine LCMS: 538 (M + H). NMR (400 MHz, DMSO-d₆) δ 12.75 (s, 1H), 9.54(d, J = 8.1 Hz, 1H), 8.29 (d, J = 5.2 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H),7.91-8.13 (m, 2H), 7.52 (d, J = 5.3 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H),5.29 (t, J = 8.6 Hz, 1H), 3.75 (s, 3H), 2.96 (d, J = 9.4 Hz, 2H), 2.55(s, 3H), 2.43 (s, 3H), 1.96 (d, J = 12.1 Hz, 3H), 1.83 (q, J = 9.5 Hz,2H), 1.46 (s, 9H). Example 71  5-tert-butyl-N-[(5S)-2-[2-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-1H- imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl]-1,2-oxazole-3- carboxamide

Chiral SFC 5-tert-butyl-N-{2-[2- (1,3,5-trimethyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl}- 1,2-oxazole-3- carboxamide LCMS: 538 (M + H). NMR(400 MHz, DMSO-d₆) δ 12.75 (s, 1H), 9.54 (d, J = 8.1 Hz, 1H), 8.29 (d, J= 5.2 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H), 7.91-8.13 (m, 2H), 7.52 (d, J =5.3 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 5.29 (t, J = 8.6 Hz, 1H), 3.75(s, 3H), 2.96 (d, J = 9.4 Hz, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 1.97 (d,J = 12.1 Hz, 3H), 1.83 (q, J = 9.5 Hz, 2H), 1.44 (s, 9H). Example 72 5-tert-butyl-N-[(5R)- 2-[2-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-1H-imidazo[4,5- b]pyridin-7-yl]-yl]- 6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-yl]-1,2-oxazole-3- carboxamide

Chiral SFC 5-tert-butyl-N-{2-[2- (1,3,5-trimethyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl}- 1,2-oxazole-3- carboxamide LCMS: 538 (M + H). NMR(400 MHz, DMSO-d₆) δ 12.75 (s, 1H), 9.54 (d, J = 8.1 Hz, 1H), 8.29 (d, J= 5.2 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H), 7.91-8.13 (m, 2H), 7.52 (d, J =5.3 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 5.29 (t, J = 8.6 Hz, 1H), 3.75(s, 3H), 2.96 (d, J = 9.4 Hz, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 1.96 (d,J = 12.1 Hz, 3H), 1.83 (q, J = 9.5 Hz, 2H), 1.46 (s, 9H). Example 73 3-tert-butyl-N-[(1S)- 6-[2-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4- tetrahydronaphthalen-1-yl]-1,2,4- oxadiazole-5- carboxamide

Chiral SFC 3-tert-butyl-N-[6-[2- (1,3,5-trimethyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5- carboxamide LCMS: 525 (M + H). ¹H NMR (400 MHz,DMSO-d₆) 12.76 (s, 1H), 9.76 (d, J = 8.7 Hz, 1H), 8.52-8.22 (m, 2H),8.22-8.03 (m, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H),5.44-5.14 (m, 1H), 3.76 (s, 3H), 2.89 (s, 2H), 2.55 (s, 3H), 2.43 (s,3H), 2.13-1.68 (m, 3H), 1.37 (s, 9H). Example 74  3-tert-butyl-N-[(1R)-6-[2-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4- tetrahydronaphthalen- 1-yl]-1,2,4-oxadiazole-5- carboxamide

Chiral SFC 3-tert-butyl-N-[6-[2- (1,3,5-trimethyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5- carboxamide LCMS: 525 (M + H). ¹H NMR (400 MHz,DMSO-d₆) 12.76 (s, 1H), 9.76 (d, J = 8.7 Hz, 1H), 8.52-8.22 (m, 2H),8.22-8.03 (m, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H),5.44-5.14 (m, 1H), 3.76 (s, 3H), 2.89 (s, 2H), 2.55 (s, 3H), 2.43 (s,3H), 2.13-1.68 (m, 3H), 1.37 (s, 9H). Example 75  3-tert-butyl-N-[(1R)-6-[2-(1-cyclopropyl- 1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-1,2,3,4- tetrahydronaphthalen- 1-yl]-1,2,4- oxadiazole-5- carboxamide

Chiral SFC Chiral SFC 3-tert-butyl-N-6-[2-(1- cyclopropyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4-tetrahydronaphthalen-1- yl]-1,2,4-oxadiazole-5- carboxamide MS: 523 (M +H). ¹H-NMR (400 MHz, DMSO-d₆, ppm): δ 13.26 (brs, 1H), 9.77 (d, J = 8.7Hz, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.27-8.04 (m, 3H), 7.46-7.33 (m,2H), 5.30-5.24 (m, 1H), 4.61 (p, J = 6.6 Hz, 1H), 2.93-2.87 (m, 2H),2.05-1.99 (m, 3H), 1.85-1.79 (m, 1H), 1.47 (d, J = 6.6 Hz, 6H),2.11-1.36 (m, 4H). Example 76  3-tert-butyl-N-[(1S)-6-[2-(1-cyclopropyl- 1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-1,2,3,4- tetrahydronaphthalen- 1-yl]-1,2,4- oxadiazole-5- carboxamide

Chiral SFC Chiral SFC 3-tert-butyl-N-6-[2-(1- cyclopropyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4-tetrahydronaphthalen-1- yl]-1,2,4-oxadiazole-5- carboxamide MS: 523 (M +H). ¹H-NMR (400 MHz, DMSO-d₆, ppm): δ 13.22 (br s, 1H), 9.77 (d, J = 8.7Hz, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.27-8.04 (m, 3H), 7.46-7.33 (m,2H), 5.29-5.23 (m, 1H), 4.61 (p, J = 6.6 Hz, 1H), 2.93-2.87 (m, 2H),2.05-1.99 (m, 3H), 1.85-1.78 (m, 1H), 1.46 (d, J = 6.6 Hz, 6H),2.11-1.36 (m, 4H). Example 77  5-tert-butyl-N-[(5S)- 2-{2-[3-methyl-1-(propan-2-yl)-1H- pyrazol-4-yl]-1H- imidazo[4,5- b]pyridin-7-yl}-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl]-1,3,4- oxadiazole-2-carboxamide

Chiral SFC 5-tert-butyl-N-[-2-{2- [3-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]- 1H-imidazo[4,5- b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-yl]- 1,3,4-oxadiazole-2- carboxamideLC/MS: (M + H) 553. HPLC: 3.74 min. 1H NMR (400 MHz, DMSO-d6) δ 13.05(s, 1H), 9.88 (d, J = 8.2 Hz, 1H), 8.40 (s, 1H), 8.32-8.13 (m, 3H), 7.50(d, J = 5.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 5.29 (t, J = 8.5 Hz, 1H),4.51 (p, J = 6.6 Hz, 1H), 2.99 (d, J = 8.9 Hz, 2H), 2.62 (s, 3H), 1.98(d, J = 10.2 Hz, 3H), 1.83 (t, J = 9.5 Hz, 2H), 1.47 (d, J = 6.7 Hz,6H), 1.43 (s, 9H). Example 78  5-tert-butyl-N-[(5R)- 2-{2-[3-methyl-1-(propan-2-yl)-1H- pyrazol-4-yl]-1H- imidazo[4,5- b]pyridin-7-yl}-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl]-1,3,4- oxadiazole-2-carboxamide

Chiral SFC 5-tert-butyl-N-[-2-{2- [3-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]- 1H-imidazo[4,5- b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-yl]- 1,3,4-oxadiazole-2- carboxamideLC/MS: (M + H) 553. HPLC: 3.74 min. 1H NMR (400 MHz, DMSO-d6) δ 13.01(s, 1H), 9.87 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.32-8.13 (m, 3H), 7.50(d, J = 5.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 5.29 (t, J = 8.5 Hz, 1H),4.51 (p, J = 6.6 Hz, 1H), 2.99 (d, J = 8.9 Hz, 2H), 2.62 (s, 3H), 1.98(d, J = 10.2 Hz, 3H), 1.83 (t, J = 9.5 Hz, 2H), 1.48 (d, J = 6.5 Hz,6H), 1.42 (s, 9H). Example 79  5-tert-butyl-N-[(5R)- 2-{2-[5-methyl-1-(oxan-4-yl)-1H- pyrazol-4-yl]-1H- imidazo[4,5- b]pyridin-7-yl}-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl]-1,3,4- oxadiazole-2-carboxamide

Chiral SFC 5-tert-butyl-N-[2-{2-[5- methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-1H- imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-yl]- 1,3,4-oxadiazole-2- carboxamideLC/MS: (M + H) 595. HPLC: 3.17 min. 1H NMR (400 MHz, DMSO-d6) δ 13.20(br.s, 1H), 9.90 (m, 1H), 8.27 (m, 2H), 8.14 (m, 2H), 7.5 (s, 1H), 7.36(m, 1H), 5.33 (s, 1H), 4.51 (s, 1H), 4.0 (2H), 3.50 (t, 2H), 3.0 (m,2H), 2.82 (s, 3H), 2.0 (m, 5H), 1.88 (m, 4H), 1.25 (m, 9H). Example 80 5-tert-butyl-N-[(5S)- 2-{2-[5-methyl-1- (oxan-4-yl)-1H-pyrazol-4-yl]-1H- imidazo[4,5- b]pyridin-7-yl}- 6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-yl]-1,3,4- oxadiazole-2- carboxamide

Chiral SFC 5-tert-butyl-N-[2-{2-[5- methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-1H- imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-yl]- 1,3,4-oxadiazole-2- carboxamideLC/MS: (M + H) 595. HPLC: 3.17 min. 1H NMR (400 MHz, DMSO-d6) δ 13.20(br.s, 1H), 9.90 (m, 1H), 8.27 (m, 2H), 8.14 (m, 2H), 7.5 (s, 1H), 7.36(m, 1H), 5.33 (s, 1H), 4.51 (s, 1H), 4.0 (2H), 3.50 (t, 2H), 3.0 (m,2H), 2.82 (s, 3H), 2.0 (m, 5H), 1.88 (m, 4H), 1.25 (m, 9H). Example 81 3-tert-butyl-N-[(5S)- 2-{2-[1-(propan-2- yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5- b]pyridin-7-yl}- 6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl]-1,2,4- oxadiazole-5- carboxamide

Chiral SFC 3-tert-butyl-N-[2-{2-[1- (propan-2-yl)-1H- pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl]- 1,2,4-oxadiazole-5- carboxamide LC/MS: (M + H)581. HPLC: 4.0 min. 1H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.97 (d,J = 7.9 Hz, 1H), 8.48 (s, 1H), 8.31-7.96 (m, 4H), 7.42 (dd, J = 32.9,6.7 Hz, 2H), 5.29 (s, 1H), 4.62 (p, J = 6.7 Hz, 1H), 3.01 (s, 2H),2.12-1.77 (m, 6H), 1.49 (dd, J = 6.7, 1.7 Hz, 6H), 1.42 (d, J = 1.7 Hz,6H). Example 82  3-tert-butyl-N-[(5R)- 2-{2-[1-(propan-2-yl)-1H-pyrazol-4-yl]- 1H-imidazo[4,5- b]pyridin-7-yl}-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- oxadiazole-5- carboxamide

Chiral SFC 3-tert-butyl-N-[2-{2-[1- (propan-2-yl)-1H- pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl]- 1,2,4-oxadiazole-5- carboxamide LC/MS: (M + H)581. HPLC: 4.0 min. 1H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.98 (d,J = 7.9 Hz, 1H), 8.46 (s, 1H), 8.31-7.96 (m, 4H), 7.42 (dd, J = 32.9,6.7 Hz, 2H), 5.29 (s, 1H), 4.62 (p, J = 6.7 Hz, 1H), 3.01 (s, 2H),2.12-1.77 (m, 6H), 1.49 (dd, J = 6.7, 1.7 Hz, 6H), 1.41 (d, J = 1.7 Hz,6H). Example 83  3-tert-butyl-N-{2-[2- (1-cyclopropyl-1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-yl}-1,2,4- oxadiazole-5- carboxamide

Method D 3-tert-butyl-N-[2-{2-[1- (propan-2-yl)-1H- pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl]- 1,2,4-oxadiazole-5- carboxamide LC/MS: (M + H)536. HPLC: 4.0 min. 1H NMR (400 MHz, DMSO-d6) d 9.98 (d, J = 7.9 Hz,1H), 8.47 (s, 1H), 8.18 (d, J = 56.8 Hz, 2H), 5.28 (s, 1H), 3.86 (dt, J= 7.3, 3.6 Hz, 1H), 2.99 (d, J = 8.3 Hz, 2H), 1.91 (d, J = 52.1 Hz, 5H),1.42 (s, 9H), 1.26-0.86 (m, 4H). Example 84  5-tert-butyl-N-(2-{2-[5-methyl-1-(propan- 2-yl)-1H-pyrazol-4- yl]-3H-imidazo[4,5-b]pyridin-7-yl}- 6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl)-1,3,4-oxadiazole-2- carboxamide

Method B 2-[2-(1-Cyclopropyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine hydrochloride LC/MS: (M + H) 553. 1H NMR (400 MHz, DMSO-d6) d9.89 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 35.5 Hz, 3H), 7.56-7.34 (m, 2H),5.29 (s, 1H), 4.75-4.55 (m, 1H), 3.07-2.65 (m, 5H), 2.10-1.73 (m, 4H),1.42 (m, 15H), 1.25-1.02 (m, 2H). Example 85  3-tert-butyl-N-{2-[2-(1-ethyl-5-methyl- 1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl}-1,2,4- oxadiazole-5-carboxamide

Method B 2-[2-(1-Ethyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine hydrochloride LC/MS: (M + H) 538. 1H NMR (400 MHz, Chloroform-d)d 8.45 (d, J = 5.4 Hz, 1H), 7.91 (d, J = 21.6 Hz, 2H), 7.61 (s, 1H),7.43 (s, 1H), 7.01 (s, 1H), 5.44 (t, J = 8.2 Hz, 1H), 4.21 (d, J = 7.2Hz, 2H), 3.05 (d, J = 9.5 Hz, 2H), 2.39 (s, 3H), 2.05 (d, J = 16.5 Hz,4H), 1.87 (s, 2H), 1.49 (d, J = 19.2 Hz, 12H). Example 86 5-tert-butyl-N-(2-{2- [3,5-dimethyl-1- (propan-2-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5- b]pyridin-7-yl}- 6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-yl)-1,3,4- oxadiazole-2- carboxamide

Method B 2-[2-(1-Isopropyl-3,5- dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H-benzocyclohepten-5- ylamine hydrochloride LC/MS: (M + H) 567. 1H NMR(400 MHz, DMSO-d6) d 12.76 (s, 1H), 9.88 (d, J = 8.2 Hz, 1H), 8.27 (s,3H), 7.58-7.30 (m, 3H), 5.29 (d, J = 9.1 Hz, 1H), 4.73-4.42 (m, 1H),3.31 (s, 9H), 2.97 (s, 3H), 2.69-2.32 (m, 10H), 1.90 (d, J = 56.1 Hz,4H), 1.53-1.29 (m, 15H). Example 87  5-tert-butyl-N-[(5R)-2-{2-[3,5-dimethyl-1- (propan-2-yl)-1H- pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin-7-yl}- 6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl]-1,3,4-oxadiazole-2- carboxamide

Chiral SFC 5-tert-butyl-N-(2-{2- [3,5-dimethyl-1- (propan-2-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl)- 1,3,4-oxadiazole-2- carboxamide LC/MS: (M + H)567. 1H NMR (400 MHz, DMSO-d6) d 12.76 (s, 1H), 9.88 (d, J = 8.2 Hz,1H), 8.27 (s, 3H), 7.58-7.30 (m, 3H), 5.29 (d, J = 9.1 Hz, 1H),4.73-4.42 (m, 1H), 3.31 (s, 9H), 2.97 (s, 3H), 2.69-2.32 (m, 10H), 1.90(d, J = 56.1 Hz, 4H), 1.53-1.26 (m, 15H). Example 88 5-tert-butyl-N-[(5S)- 2-{2-[3,5-dimethyl-1- (propan-2-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5- b]pyridin-7-yl}- 6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-yl]-1,3,4- oxadiazole-2- carboxamide

Chiral SFC 5-tert-butyl-N-(2-{2- [3,5-dimethyl-1- (propan-2-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl)- 1,3,4-oxadiazole-2- carboxamide LC/MS: (M + H)567. 1H NMR (400 MHz, DMSO-d6) d 12.76 (s, 1H), 9.88 (d, J = 8.2 Hz,1H), 8.27 (s, 3H), 7.58-7.30 (m, 3H), 5.29 (d, J = 9.1 Hz, 1H),4.73-4.42 (m, 1H), 3.31 (s, 9H), 2.97 (s, 3H), 2.69-2.32 (m, 10H), 1.90(d, J = 56.1 Hz, 4H), 1.53-1.29 (m, 15H). Example 89 5-tert-butyl-N-[(5S)- 2-[2-(5-ethyl-1- methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5- b]pyridin-7-yl]- 6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-yl]-1,3,4- oxadiazole-2- carboxamide

Chiral SFC 5-tert-butyl-N-[2-[2-(5- ethyl-1-methyl-1H- pyrazol-3-yl)-1H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl]- 1,3,4-oxadiazole-2- carboxamide LC/MS: (M + H)539. HPLC: 4.18 (97%) min. 1H NMR (400 MHz, DMSO-d6) δ 9.79 (d, 1H),8.30 (m, 2H), 8.23 (m, 1H), 8.02 (s, 1H), 7.49 (m, 2H), 6.75 (s, 1H),5.25 (s, 1H), 3.84 (s, 3H), 2.99 (m, 2H), 2.45 (m, 2H), 2.02 (m, 3H),1.79 (m, 2H), 1.47 (m, 10H), 1.25 (m, 3H), 0.99 (d, 2H). Example 90 5-tert-butyl-N-[(5R)- 2-[2-(5-ethyl-1- methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5- b]pyridin-7-yl]- 6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-yl]-1,3,4- oxadiazole-2- carboxamide

Chiral SFC 5-tert-butyl-N-[2-[2-(5- ethyl-1-methyl-1H- pyrazol-3-yl)-1H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl]- 1,3,4-oxadiazole-2- carboxamide LC/MS: (M + H)539. HPLC: 4.18 (97%) min. 1H NMR (400 MHz, DMSO-d6) δ 9.79 (d, 1H),8.30 (m, 2H), 8.23 (m, 1H), 8.01 (s, 1H), 7.49 (m, 2H), 6.75 (s, 1H),5.25 (s, 1H), 3.83 (s, 3H), 2.99 (m, 2H), 2.45 (m, 2H), 2.03 (m, 3H),1.79 (m, 2H), 1.47 (m, 10H), 1.23 (m, 3H), 1.00 (d, 2H). Example 91 5-tert-butyl-N-(2-{2- [1-(propan-2-yl)-1H- pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)-1,2-oxazole-3- carboxamide

Method B 2-[2-(1-Isopropyl-1H- pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5- ylamine LC/MS: (M + H)538. 1H NMR (400 MHz, Chloroform-d) d 8.49-7.89 (m, 6H), 7.58-7.33 (m,2H), 6.47 (s, 1H), 5.47 (s, 1H), 4.61 (s, 0H), 3.07 (s, 1H), 2.16-1.83(m, 4H), 1.77-1.51 (m, 4H), 1.41 (s, 15H). Example 92 5-tert-butyl-N-[(5R)- 2-{2-[1-(propan-2- yl)-1H-imidazo[4,5-b]pyridin-7-yl}- 6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl]-1,2-oxazole-3- carboxamide

Chiral SFC Chiral SFC 5-tert-butyl-N-[2-{2-[1- (propan-2-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl]- 1,2-oxazole-3- carboxamide LC/MS: (M + H) 538. ¹HNMR (400 MHz, Methanol-d₄) δ 10.11 (d, J = 8.0 Hz, 1H), 9.30 (s, 1H),9.10-8.92 (m, 2H), 8.82 (s, 1H), 8.33-8.12 (m, 3H), 6.09 (t, J = 8.9 Hz,1H), 5.51-5.34 (m, 1H), 4.38-4.07 (m, 2H), 2.90-2.53 (m, 6H), 2.29 (d, J= 6.5 Hz, 6H), 2.18 (s, 9H). Example 93  5-tert-butyl-N-[(5S)-2-{2-[1-(propan-2- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl]-1,2-oxazole-3- carboxamide

Chiral SFC Chiral SFC 5-tert-butyl-N-[2-{2-[1- (propan-2-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl]- 1,2-oxazole-3- carboxamide LC/MS: (M + H) 538. ¹HNMR (400 MHz, Methanol-d₄) δ 10.11 (d, J = 8.0 Hz, 1H), 9.30 (s, 1H),9.10-8.92 (m, 2H), 8.82 (s, 1H), 8.33-8.12 (m, 3H), 6.09 (t, J = 8.9 Hz,1H), 5.51-5.34 (m, 1H), 4.38-4.07 (m, 2H), 2.90-2.53 (m, 6H), 2.29 (d, J= 6.5 Hz, 6H), 2.18 (s, 9H). Example 94  5-tert-butyl-N-{2-[2-(1,3,5-trimethyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl}-1,2-oxazole-3- carboxamide

Method B 2-[2-(1,3,5-Trimethyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine LC/MS: (M + H) 538. ¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (d, J = 5.2Hz, 1H), 7.06 (s, 2H), 6.65 (d, J = 7.9 Hz, 2H), 5.71 (s, 1H), 5.54 (s,1H), 3.02 (s, 3H), 2.49-2.17 (m, 2H), 1.80-1.55 (m, 6H), 1.39-0.97 (m,4H), 0.65-0.50 (m, 12H). Example 95  3-tert-butyl-N-[(1S)-6-{2-[3,5-dimethyl-1- (propan-2-yl)-1H- pyrazol-4-yl]-1H- imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4- tetrahydronaphthalen- 1-yl]-1,2,4-oxadiazole-5- carboxamide

Chiral SFC 3-tert-butyl-N-[6-{2- [3,5-dimethyl-1- (propan-2-yl)-1H-pyrazol-4-yl]-1H- imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4-tetrahydronaphthalen-1- yl]-1,2,4-oxadiazole-5- carboxamide LC/MS: (M +H) 553. HPLC: 3.69 min. 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz,DMSO-d6) δ 9.75 (s, 1H), 8.31-8.05 (m, 3H), 7.50 (m, 2H), 5.25 (s, 1H),4.51 (m, 1H), 2.89 (m, 5H), 2.51 (s, 3H), 2.48 (s, 3H), 1.99 (m, 4H),1.34 (m, 6H), 1.27 (s, 9H). Example 96  3-tert-butyl-N-[(1R)-6-{2-[3,5-dimethyl-1- (propan-2-yl)-1H- pyrazol-4-yl]-1H- imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4- tetrahydronaphthalen- 1-yl]-1,2,4-oxadiazole-5- carboxamide

Chiral SFC 3-tert-butyl-N-[{2-[3,5- dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]- 1H-imidazo[4,5- b]pyridin-7-yl}-1,2,3,4-tetrahydronaphthalen-1- yl]-1,2,4-oxadiazole-5- carboxamide LC/MS: (M +H) 553. HPLC: 3.69 min. 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz,DMSO-d6) δ 9.75 (s, 1H), 8.31-8.05 (m, 3H), 7.50 (m, 2H), 5.25 (s, 1H),4.51 (m, 1H), 2.90 (m, 5H), 2.52 (s, 3H), 2.48 (s, 3H), 2.0 (m, 4H),1.32 (m, 6H), 1.29 (s, 9H) Example 97  3-tert-butyl-N-{2-[2-(1-ethyl-5-methyl- 1H-pyrazol-3-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl}-1,2,4- oxadiazole-5-carboxamide

Method B 2-[2-(1-Ethyl-5-methyl- 1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine hydrochloride LC/MS: (M + H) 539. ¹H NMR (400 MHz, Chloroform-d)δ 11.48 (s, 1H), 8.53-8.39 (m, 1H), 8.15-8.01 (m, 2H), 7.64-7.38 (m,3H), 7.28 (d, J = 2.1 Hz, 1H), 6.86 (s, 1H), 5.46 (t, J = 8.3 Hz, 1H),4.33-4.15 (m, 2H), 3.33-3.03 (m, 2H), 2.40 (s, 3H), 2.21-1.75 (m, 6H),1.60-1.30 (m, 12H). Example 98  N-[(5R)-2-{2-[3- methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridin-7-yl}-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl]-4,5,6,7- tetrahydro-1-benzothiophene-2- carboxamide

Chiral SFC N-[2-{2-[3-methyl-1- (propan-2-yl)-1H- pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl]- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide LC/MS: (M + H) 565. ¹H NMR (400 MHz, Methanol-d₄) δ 8.29 (s,1H), 8.09 (s, 1H), 7.58 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 5.38 (d, J =10.0 Hz, 1H), 4.76-4.62 (m, 1H), 3.18-2.93 (m, 2H), 2.81 (d, J = 10.6Hz, 5H), 2.69 (t, J = 6.0 Hz, 2H), 2.19-1.77 (m, 10H), 1.51 (d, J = 6.6Hz, 6H). Example 99  N-[(5R)-2-{2-[3- methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridin-7-yl}-6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl]-4,5,6,7- tetrahydro-1-benzothiophene-2- carboxamide

Chiral SFC N-[2-{2-[3-methyl-1- (propan-2-yl)-1H- pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl]- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide LC/MS: (M + H) 565. ¹H NMR (400 MHz, Methanol-d₄) δ 8.29 (s,1H), 8.09 (s, 1H), 7.58 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 5.38 (d, J =10.0 Hz, 1H), 4.76-4.61 (m, 1H), 3.19-2.92 (m, 2H), 2.80 (d, J = 10.6Hz, 5H), 2.68 (t, J = 6.0 Hz, 2H), 2.19-1.76 (m, 10H), 1.50 (d, J = 6.6Hz, 6H). Example 100 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{(R)- 6-[2-(1-methyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

SFC LC/MS: (M + H) 497. HPLC: 3.28 min. 1H NMR (400 MHz, DMSO-d6) δ13.30 (br.s, 1H), 9.87 (d, 1H), 8.50 (s, 1H), 8.27 (m, 1H), 8.12 (m,3H), 7.49 (m, 2H), 5.33 (s, 1H), 3.98 (s, 3H), 2.94 (m, 2H), 2.02 (m,3H), 1.79 (m, 1H), 1.40 (s, 9H) Example 101 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid (6-{2- [1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4- yl]-3H-imidazo[4,5- b]pyridin-7-yl}-1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 7-Bromo-2-[1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridine and 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylicacid [6- (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-amide LC/MS: (M + H) 567. HPLC:3.44 min. 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.47 (s, 1H),8.04-8.21 (m, 3H), 7.29 (m, 2H), 5.27 (m, 1H), 4.50 (m, 1H), 3.99 (m,2H), 2.88 (m, 2H), 2.0 (m, 7H), 1.37 (s, 9H). Example 1021-tert-Butyl-1H- [1,2,3]triazole-4- carboxylic acid ((R)-6-{2-[1-(tetrahydro- pyran-4-yl)-1H- pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

SFC LC/MS: (M + H) 566. HPLC: 3.04 min. 1H NMR (400 MHz, DMSO-d6) δ 8.77(s, 1H), 8.25 (d, 1H), 8.27 (s, 1H), 8.10 (m, 3H), 7.5 (m, 2H), 5.25 (m,1H), 4.5 (m, 1H), 4.0 (m, 2H), 2.57 (m, 2H), 2.0 (m, 6H), 1.75 (m, 1H),1.68 (s, 9H). Example 103 3-(1-Methyl- cyclopropyl)-[1,2,4]oxadiazole-5- carboxylic acid {6-[2- (1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4-tetrahydro-naphthalen-1-yl}- amide

Method C -(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5- carboxylic acid[6- (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2- yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amide and 7-Bromo-2-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridine LC/MS: (M + H) 495. HPLC: 2.99 min. 1HNMR (400 MHz, DMSO-d6) δ 9.67 (m, 1H), 8.38 (m, 1H), 8.24 (m, 1H), 8.15(m, 2H), 7.44 (m, 1H), 7.31 (m, 1H), 5.25 (s, 1H), 3.92 (s, 3H), 2.81(m, 2H), 2.0 (m, 4H), 1.5 (s, 3H), 1.22 (m, 2H), 1.0 (s, 2H). Example104 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylic acid {6-[2-(1-methyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylic acid [6-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2- yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amide and 7-Bromo-2-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridine LC/MS: (M + H) 497. HPLC: 2.93 min. 1HNMR (400 MHz, DMSO-d6) δ 9.67 (m, 1H), 8.49 (s, 1H), 8.28 (s, 1H), 8.19(s, 1H), 8.0 (m, 2H), 7.44 (m, 2H), 5.25 (m, 1H), 2.77 (m, 2H), 2.0 (m,4H), 1.41 (s, 9H). Example 105 5-tert-Butyl- [1,3,4]oxadiazole-2-carboxylic acid {6-[2- (1-methyl-1H- pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method B 2-{2-[1-(Tetrahydro- pyran-4-yl)-1H- pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylaminehydrochloride LC/MS: (M + H) 581. HPLC: 4.0 min. 1H NMR (400 MHz,DMSO-d6) δ 13.20 (br.s, 1H), 9.99 (m, 1H), 8.51 (s, 1H), 8.0-8.25 (m,3H), 7.20 (m, 2H), 5.30 (s, 1H), 4.51 (s, 1H), 4.0 (2H), 3.49 (m, 2H),3.0 (m, 2H), 2.1 (m, 9H), 1.19 (s, 10H). Example 106 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid {2-[2- (1-isopropyl-1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H-benzocyclohepten-5- yl}-amide

Method B 2-[2-(1-Isopropyl-1H- pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5- ylamine hydrochlorideLC/MS: (M + H) 581. HPLC: 4.0 min. 1H NMR (400 MHz, DMSO-d6) δ 13.20 (s,1H), 9.97 (d, J = 7.9 Hz, 1H), 8.48 (s, 1H), 8.31-7.96 (m, 4H), 7.42(dd, J = 32.9, 6.7 Hz, 2H), 5.29 (s, 1H), 4.62 (p, J = 6.7 Hz, 1H), 3.01(s, 2H), 2.12-1.77 (m, 6H), 1.49 (dd, J = 6.7, 1.7 Hz, 6H), 1.42 (d, J =1.7 Hz, 10H). Example 107 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylicacid {6-[2- (1,5-dimethyl-1H- pyrazol-3-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid [6-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2- yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amide and 7-Bromo-2-(1,5- dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5- b]pyridine LC/MS: (M + H) 511. HPLC: 3.55 min. 1HNMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.08-8.26 (m, 2H), 7.37 (m, 2H),6.75 (s, 1H), 5.23 (s, 1H), 3.79 (s, 3H), 2.82 (m, 2H), 2.29 (s, 3H),2.0 (m, 3H), 1.82 (s, 1H), 1.37 (s, 9H). Example 108 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid {6-[2- (5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4-tetrahydro-naphthalen-1-yl}- amide

Method C Butyl- [1,2,4]oxadiazole-5- carboxylic acid [6-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2- yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amide and 7-Bromo-2-(5- ethyl-1-methyl-1H-pyrazol-3-yl)-3H- imidazo[4,5-b]pyridine LC/MS: (M + H) 525. HPLC: 3.77min. 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.29 (m, 1H), 8.08-8.24(m, 2H), 7.40 (m, 2H), 6.75 (s, 1H), 5.25 (s, 1H), 3.81 (s, 3H), 2.82(m, 2H), 2.74 (m, 2H), 2.0 (m, 3H), 1.82 (s, 1H), 1.37 (s, 9H), 1.25 (s,3H). Example 109 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{2-[2- (1-methyl-1H- pyrazol-3-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(1-Methyl-1H- pyrazol-3-yl)-3H- imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5- ylamine hydrochlorideLC/MS: (M + H) 511. HPLC: 3.54 min. 1H NMR (400 MHz, DMSO-d6) δ 13.5 (s,1H), 10 (s, 1H), 8.08-8.24 (m, 3H), 7.90 (s, 1H), 7.40 (m, 2H), 6.97 (s,1H), 5.17 (s, 1H), 4.0 (s, 3H), 3.0 (s, 2H), 2.0 (m, 5H), 1.23 (s, 10H).Example 110 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {2-[2-(1,5-dimethyl-1H- pyrazol-3-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method A 2-[2-(1,5-Dimethyl-1H- pyrazol-3-yl)-3H-imidazol[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H-benzocyclohepten-5- ylamine hydrochloride LC/MS: (M + H) 525. HPLC: 3.65min. 1H NMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H), 9.97 (s, 1H), 8.08-8.24(m, 3H), 7.50 (m, 2H), 6.83 (s, 1H), 5.36 (s, 1H), 3.90 (s, 3H), 3.0 (s,2H), 2.41 (s, 3H), 2.0 (m, 5H), 1.23 (s, 10H). Example 111 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid {6-[2- (1,5-dimethyl-1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4-tetrahydro-naphthalen-1-yl}- amide

Method C 7-Bromo-2-(1,5- dimethyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridine and 3-tert- butyl-N-[6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2,3,4- tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5- carboxamide LC/MS: (M + H) 511. HPLC: 3.52 min.1H NMR (400 MHz, DMSO-d6) δ 9.87 (m, 1H), 8.29 (m, 1H), 8.04 (m, 2H),7.49 (m, 2H), 6.75 (s, 1H), 5.31 (s, 1H), 3.82 (s, 3H), 2.94 (m, 2H),2.38 (s, 3H), 2.0 (m, 3H), 1.82 (s, 1H), 1.20 (s, 9H) Example 1123-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {6-[2-(1-isopropyl-5- methyl-1H-pyrazol-3- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid [6-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2- yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amide and 7-Bromo-2-(1- isopropyl-5-methyl-1H-pyrazol-3-yl)-3H- imidazo[4,5-b]pyridine LC/MS: (M + H) 539. HPLC: 3.89min. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (m, 1H), 8.20 (m, 1H), 8.04 (m,2H), 7.49 (m, 2H), 6.63 (s, 1H), 5.33 (s, 1H), 4.55 (m, 1H), 2.94 (m,2H), 2.38 (s, 3H), 2.0 (m, 3H), 1.82 (s, 1H), 1.25 (m, 6H), 1.20 (s, 9H)Example 113 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {(S)-6-[2-(1-isopropyl-3- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

SFC separation LC/MS: (M + H) 539. HPLC: 4.18 min. 1H NMR (400 MHz,DMSO-d6) δ 9.75 (d, 1H), 8.43 (m, 2H), 8.27 (m, 1H), 8.12 (m, 1H), 7.49(m, 2H), 5.25 (s, 1H), 4.5 (m, 1H), 2.94 (m, 2H), 2.65 (s, 3H), 2.02 (m,3H), 1.79 (m, 1H), 1.51 (m, 6H), 1.33 (s, 9H) Example 114 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid {(R)- 6-[2-(1-isopropyl-3-methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5- b]pyridin-7-yl]-1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

SFC separation LC/MS: (M + H) 539. HPLC: 4.18 min. 1H NMR (400 MHz,DMSO-d6) δ 9.75 (d, 1H), 8.43 (m, 2H), 8.27 (m, 1H), 8.12 (m, 1H), 7.49(m, 2H), 5.25 (s, 1H), 4.5 (m, 1H), 2.94 (m, 2H), 2.65 (s, 3H), 2.02 (m,3H), 1.79 (m, 1H), 1.51 (m, 6H), 1.33 (s, 9H) Example 115 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid ((S)- 6-{2-[3-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

SFC separation LC/MS: (M + H) 581. HPLC: 3.55 min. 1H NMR (400 MHz,DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 9.75 (m, 1H),8.31-8.05 (m, 4H), 7.50 (m, 2H), 5.27 (m, 1H), 4.46 (m, 1H), 4.0 (m,2H), 3.5 (t, 2H), 2.90 (m, 2H), 2.52 (s, 3H), 2.48 (s, 3H), 2.0 (m, 8H),1.36 (s, 9H). Example 116 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylicacid {2-[2- (1,3,5-trimethyl-1H- pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(1,3,5-Trimethyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine hydrochloride LC/MS: (M + H) 539. HPLC: 3.07 min. 1H NMR (400MHz, DMSO-d6) δ 9.89 (m, 1H), 8.0-8.25 (m, 3H), 7.50 (m, 1H), 7.42 (m,1H), 5.30 (s, 1H), 3.73 (s, 3H), 3.0 (m, 2H), 2.5 (m, 6H), 2.0 (m, 5H),1.19 (s, 10H). Example 117 3-(1-Methyl- cyclopropyl)-[1,2,4]oxadiazole-5- carboxylic acid {2-[2- (1-isopropyl-5-methyl-1H-pyrazol-3- yl)-3H-imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(1-Isopropyl-5- methyl-1H-pyrazol-3- yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylaminehydrochloride LC/MS: (M + H) 551. HPLC: 3.74 min. 1H NMR (400MHz, DMSO-d6) δ 9.5 (m, 1H), 8.0-8.45 (m, 3H), 7.5 (m, 2H), 6.75 (s,1H), 5.26 (m, 1H), 4.61 (m, 1H), 3.0 (m, 2H), 2.29 (s, 3H), 2.0 (m, 5H),1.5 (m, 12H), 1.24 (s, 2H). Example 118 5-tert-Butyl-[1,3,4]oxadiazole-2- carboxylic acid {2-[2- (1-isopropyl-3-methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(1-Isopropyl-3- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5- ylaminehydrochloride LC/MS: (M + H) 553. HPLC: 3.74 min. 1H NMR (400 MHz,DMSO-d6) δ 13.05 (s, 1H), 9.88 (d, J = 8.2 Hz, 1H), 8.40 (s, 1H),8.32-8.13 (m, 3H), 7.50 (d, J = 5.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H),5.29 (t, J = 8.5 Hz, 1H), 4.51 (p, J = 6.6 Hz, 1H), 2.99 (d, J = 8.9 Hz,2H), 2.62 (s, 3H), 1.98 (d, J = 10.2 Hz, 3H), 1.83 (t, J = 9.5 Hz, 2H),1.47 (d, J = 6.7 Hz, 6H), 1.43 (s, 10H). Example 119 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid {(S)- 6-[2-(1-isopropyl-1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4-tetrahydro-naphthalen-1-yl}- amide

SFC LC/MS: (M + H) 525. HPLC: 3.62 min.1H NMR (400 MHz, DMSO-d6) δ 1HNMR (400 MHz, DMSO-d6) δ 9.75 (m, 1H), 8.49-8.05 (m, 4H), 7.44 (m, 2H),5.27 (m, 1H), 4.58 (m, 1H), 2.90 (m, 2H), 2.0 (m, 4H), 1.50 (m, 6H),1.36 (s, 9H). Example 120 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylicacid (2-{2- [5-methyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 6,7,8,9-tetrahydro- 5H-benzocyclohepten-5- yl)-amide

Method B 2-{2-[5-Methyl-1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine hydrochloride LC/MS: (M + H) 595. HPLC: 3.17 min. 1H NMR (400MHz, DMSO-d6) δ 13.20 (br.s, 1H), 9.90 (m, 1H), 8.27 (m, 2H), 8.14 (m,2H), 7.5 (s, 1H), 7.36 (m, 1H), 5.33 (s, 1H), 4.51 (s, 1H), 4.0 (2H),3.50 (t, 2H), 3.0 (m, 2H), 2.82 (s, 3H), 2.0 (m, 5H), 1.88 (m, 4H), 1.25(m, 10H). Example 121 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylic acid{(R)- 2-[2-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

SFC LC/MS: (M + H) 539. HPLC: 3.07 min. 1H NMR (400 MHz, DMSO-d6) δ 9.89(m, 1H), 8.0-8.25 (m, 3H), 7.50 (m, 1H), 7.42 (m, 1H), 5.30 (s, 1H),3.73 (s, 3H), 3.0 (m, 2H), 2.5 (m, 6H), 2.0 (m, 5H), 1.19 (s, 10H).Example 122 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylic acid {(S)-2-[2-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

SFC LC/MS: (M + H) 539. HPLC: 3.07 min. 1H NMR (400 MHz, DMSO-d6) δ 9.89(m, 1H), 8.0-8.25 (m, 3H), 7.50 (m, 1H), 7.42 (m, 1H), 5.30 (s, 1H),3.73 (s, 3H), 3.0 (m, 2H), 2.5 (m, 6H), 2.0 (m, 5H), 1.19 (s, 10H).Example 123 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5- carboxylicacid {(R)- 2-[2-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

LC/MS: (M + H) 537. HPLC: 3.33 min. 1H NMR (400 MHz, DMSO-d6) δ 1H NMR(400 MHz, DMSO-d6) δ 12. 83 (m, 1H), 9.95 (s, 1H), 8.31 (m, 2H),7.50-7.24 (m, 2H), 5.34 (s, 1H), 3.74 (s, 3H), 2.99 (s, 2H), 2.0 (m,5H), 1.52 (s, 3H), 1.31-1.21 (m, 3H), 1.02 (m, 2H). Several proton peaksExample 124 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {(R)-6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

SFC LC/MS: (M + H) 539. HPLC: 4.22 min. 1H NMR (400 MHz, DMSO-d6) δ 8.24(m, 1H), 8.05 (m, 2H), 7.50 (m, 2H), 5.44 (m, 1H), 4.77 (m, 1H), 3.0 (m,2H), 2.74 (m, 3H), 2.0 (m, 4H), 1.52 (m, 6H), 1.46 (s, 9H). Example 1253-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {(S)-6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

SFC LC/MS: (M + H) 539. HPLC: 4.22 min. ¹H NMR (400 MHz, DMSO-d6) δ 8.24(m, 1H), 8.05 (m, 2H), 7.50 (m, 2H), 5.44 (m, 1H), 4.77 (m, 1H), 3.0 (m,2H), 2.74 (m, 3H), 2.0 (m, 4H), 1.52 (m, 6H), 1.46 (s, 9H). Example 1263-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {(S)-6-[2-(1-methyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

SFC LC/MS: (M + H) 497. HPLC: 3.28 min. 1H NMR (400 MHz, DMSO-d6) δ13.30 (br.s, 1H), 9.87 (d, 1H), 8.50 (s, 1H), 8.27 (m, 1H), 8.12 (m,3H), 7.49 (m, 2H), 5.33 (s, 1H), 3.98 (s, 3H), 2.94 (m, 2H), 2.02 (m,3H), 1.79 (m, 1H), 1.40 (s, 9H) Example 127 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid (6-{2- [5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid [6-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2- yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amide and 7-Bromo-2-[5- methyl-1-(tetrahydro-pyran-4-yl)-1H- pyrazol-4-yl]-3H- imidazo[4,5-b]pyridine LC/MS: (M + H)581. HPLC: 3.53 min.¹H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz,DMSO-d6) δ 13.30 (s, 1H), 9.83 (s, 1H), 8.31-8.05 (m, 4H), 7.50 (m, 2H),5.39 (s, 1H), 4.51 (m, 1H), 4.0 (m, 2H), 3.50 (t, 2H), 2.90 (m, 5H), 2.0(m, 5H), 1.85 (m, 3H), 1.43 (s, 9H). Example 128 3-(1-Methyl-cyclopropyl)- [1,2,4]oxadiazole-5- carboxylic acid {2-[2-(1,3,5-trimethyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(1,3,5-Trimethyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine hydrochloride LC/MS: (M + H) 537. HPLC: 3.33 min. 1H NMR (400MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12. 83 (m, 1H), 9.95 (s,1H), 8.31 (m, 2H), 7.50-7.24 (m, 2H), 5.34 (s, 1H), 3.74 (s, 3H), 2.99(s, 2H), 2.0 (m, 5H), 1.52 (s, 3H), 1.31-1.21 (m, 3H), 1.02 (m, 2H).Several proton peaks overlap with solvent peak. Example 1293-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {6-[2- (1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4-tetrahydro-naphthalen-1-yl}- amide

Method B 6-[2-(1-Methyl-1H- pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-ylamine hydrochloride LC/MS:(M + H) 497. HPLC: 3.28 min. 1H NMR (400 MHz, DMSO-d6) δ 13.30 (br.s,1H), 9.87 (d, 1H), 8.50 (s, 1H), 8.27 (m, 1H), 8.12 (m, 3H), 7.49 (m,2H), 5.33 (s, 1H), 3.98 (s, 3H), 2.94 (m, 2H), 2.02 (m, 3H), 1.79 (m,1H), 1.40 (s, 9H) Example 130 3-tert-Butyl- [1,2,4]oxadiazole-5-carboxylic acid {6-[2- (1-isopropyl-3- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4-tetrahydro-naphthalen-1-yl}- amide

Method C 7-Bromo-2-(1- isopropyl-3-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine and 3-tert-butyl-N-[6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,2,3,4- tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5- carboxamide LC/MS: (M + H) 539. HPLC: 4.18 min.1H NMR (400 MHz, DMSO-d6) δ 9.75 (d, 1H), 8.43 (m, 2H), 8.27 (m, 1H),8.12 (m, 1H), 7.49 (m, 2H), 5.25 (s, 1H), 4.5 (m, 1H), 2.94 (m, 2H),2.65 (s, 3H), 2.02 (m, 3H), 1.79 (m, 1H), 1.51 (m, 6H), 1.33 (s, 9H)Example 131 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylic acid {2-[2-(5-ethyl-1-methyl- 1H-pyrazol-3-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(5-Ethyl-1-methyl- 1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylaminehydrochloride LC/MS: (M + H) 539. HPLC: 4.18 (97%) min. 1H NMR(400 MHz, DMSO-d6) δ 9.79 (d, 1H), 8.30 (m, 2H), 8.23 (m, 1H), 8.02 (s,1H), 7.49 (m, 2H), 6.75 (s, 1H), 5.25 (s, 1H), 3.84 (s, 3H), 2.99 (m,2H), 2.45 (m, 2H), 2.02 (m, 3H), 1.79 (m, 2H), 1.47 (m, 10H), 1.25 (m,3H), 0.99 (d, 2H). Example 132 3-tert-Butyl- [1,2,4]oxadiazole-5-carboxylic acid {2-[2- (1-isopropyl-3- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H-benzocyclohepten-5- yl}-amide

Method B 2-[2-(1-Isopropyl-3- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylaminehydrochloride LC/MS: (M + H) 539. HPLC: 4.18 min. 1H NMR (400MHz, DMSO-d6) δ 13.07 (s, 1H), 9.98 (m, 1H), 8.10-8.43 (m, 4H), 7.50 (m,2H), 5.32 (m, 1H), 4.51 (m, 1H), 3.0 (m, 2H), 2.0 (m, 3H), 1.88 (m, 2H),1.5 (m, 6H), 1.48 (m, 10H). Example 133 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid {2-[2- (5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 6,7,8,9-tetrahydro-5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(5-Ethyl-1-methyl- 1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylaminehydrochloride LC/MS: (M + H) 539. HPLC: 3.86 min. 1H NMR (400MHz, DMSO-d6) δ 13.37 (bs, 1H), 9.98 (m, 1H), 8.0-8.4 (m, 3H), 7.50 (m,2H), 6.75 (m, 1H), 5.30 (m, 1H), 3.86 (s, 3H), 3.0 (m, 2H), 2.69 (m,2H), 2.0 (m, 3H), 1.88 (m, 2H), 1.48 (m, 10H), 1.16 (m, 3H). Example 1343-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5- carboxylic acid {2-[2-(1-isopropyl-3- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(1-Isopropyl-3- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5- ylaminehydrochloride LC/MS: (M + H) 551. HPLC: 3.52 min. 1H NMR (400 MHz,DMSO-d6) δ 13.00 (bs, 1H), 9.50 (m, 1H), 8.0-8.4 (m, 4H), 7.50 (m, 2H),5.32 (m, 1H), 4.50 (m, 1H), 3.0 (m, 2H), 2.53 (s, 3H), 2.0 (m, 3H), 1.50(s, 3H), 1.48 (m, 9H) Example 135 3-(1-Methyl- cyclopropyl)-[1,2,4]oxadiazole-5- carboxylic acid {2-[2- (1-ethyl-3,5-dimethyl-1H-pyrazol- 4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(1-Isopropyl-3- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylaminehydrochloride LC/MS: (M + H) 551. HPLC: 3.67 min. 1H NMR (400MHz, DMSO-d6) δ 9.85 (m, 1H), 9.50 (m, 1H), 8.0-8.4 (m, 4H), 7.50 (m,2H), 5.25 (m, 1H), 4.50 (m, 1H), 3.0 (m, 2H), 2.56 (s, 3H), 2.0 (m, 5H),1.50 (s, 3H), 1.48 (m, 7H), 1.25 (m, 2H), 1.0 (m, 2H) Example 1363-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {2-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(1-Isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylaminehydrochloride LC/MS: (M + H) 553. HPLC: 4.35 min. 1H NMR (400MHz, DMSO-d6) δ 13.10 (br.s, 1H), 10.01 (m, 1H), 8.0-8.4 (m, 4H), 7.50(m, 2H), 5.31 (m, 1H), 4.55 (m, 1H), 3.0 (m, 2H), 2.77 (s, 3H), 2.0 (m,5H), 3H), 1.48 (m, 16H) Example 137 3-tert-Butyl- [1,2,4]oxadiazole-5-carboxylic acid ((R)- 6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridin-7-yl}-1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

SFC LC/MS: (M + H) 581. HPLC: 3.53 min. 1H NMR (400 MHz, DMSO-d6) δ 1HNMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.83 (s, 1H), 8.31-8.05 (m, 4H),7.50 (m, 2H), 5.39 (s, 1H), 4.51 (m, 1H), 4.0 (m, 2H), 3.50 (t, 2H),2.90 (m, 5H), 2.0 (m, 5H), 1.85 (m, 3H), 1.43 (s, 9H). Example 1383-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid ((S)-6-{2-[5-methyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)-amide

SFC LC/MS: (M + H) 581. HPLC: 3.53 min. 1H NMR (400 MHz, DMSO-d6) δ 1HNMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.83 (s, 1H), 8.31-8.05 (m, 4H),7.50 (m, 2H), 5.39 (s, 1H), 4.51 (m, 1H), 4.0 (m, 2H), 3.50 (t, 2H),2.90 (m, 5H), 2.0 (m, 5H), 1.85 (m, 3H), 1.43 (s, 9H). Example 1393-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {6-[2-(1-isopropyl-3,5- dimethyl-1H-pyrazol- 4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 7-Bromo-2-(1- isopropyl-3,5-dimethyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine and 3-tert- Butyl[1,2,4]oxadiazole- 5-carboxylicacid [6- (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-amide LC/MS: (M + H) 553. HPLC:3.69 min.¹H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 9.75(s, 1H), 8.31-8.05 (m, 3H), 7.50 (m, 2H), 5.25 (s, 1H), 4.51 (m, 1H),2.90 (m, 5H), 2.52 (s, 3H), 2.48 (s, 3H), 2.0 (m, 4H), 1.32 (m, 6H),1.29 (s, 9H). Example 140 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylicacid (6-{2- [3,5-dimethyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)-amide

Method C 7-Bromo-2-[3,5- dimethyl-1-(tetrahydro- pyran-4-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridine and 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid [6- (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- yl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-amideLC/MS: (M + H) 595. HPLC: 3.92 min. 1H NMR (400 MHz, DMSO-d6) δ 1H NMR(400 MHz, DMSO-d6) δ 12.77 (brs, 1H), 9.70 (m, 1H), 8.31-8.05 (m, 3H),7.50 (m, 2H), 5.25 (s, 1H), 4.51 (m, 1H), 4.0 (m, 2H), 3.5 (t, 2H), 2.90(m, 5H), 2.52 (s, 3H), 2.48 (s, 3H), 2.0 (m, 5H), 1.81 (m, 3H), 1.29 (s,9H). Example 141 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{(S)- 2-[2-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

SPC LC/MS: (M + H) 539. HPLC: 3.38 min. 1H NMR (400 MHz, DMSO-d6) δ 1HNMR (400 MHz (400 MHz, DMSO-d6) δ 12.77 (brs, 1H), 9.70 (m, 1H),8.31-8.05 (m, 3H), 7.50 (m, 2H), 5.25 (s, 1H), 4.51 (m, 1H), 4.0 (m,2H), 3.5 (t, 2H), 2.90 (m, 5H), 2.52 (s, 3H), 2.48 (s, 3H), 2.0 (m, 5H),1.81 (m, 3H), 1.29 (s, 9H). Example 142 3-tert-Butyl-[1,2,4]oxadiazole-5- carboxylic acid {(R)- 2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 6,7,8,9-tetrahydro-5H- benzocyclohepten-5- yl}-amide

SFC LC/MS: (M + H) 539. HPLC: 3.38 min. 1H NMR (400 MHz, DMSO-d6) δ 1HNMR (400 MHz (400 MHz, DMSO-d6) δ 12.77 (brs, 1H), 9.70 (m, 1H),8.31-8.05 (m, 3H), 7.50 (m, 2H), 5.25 (s, 1H), 4.51 (m, 1H), 4.0 (m,2H), 3.5 (t, 2H), 2.90 (m, 5H), 2.52 (s, 3H), 2.48 (s, 3H), 2.0 (m, 5H),1.81 (m, 3H), 1.29 (s, 9H). Example 143 3-(1-Methyl- cyclopropyl)-[1,2,4]oxadiazole-5- carboxylic acid {2-[2- (1,3,5-trimethyl-1H-pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H-benzocyclohepten-5- yl}-amide

Method B 2-[2-(1,3,5-Trimethyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ylamine hydrochloride LC/MS: (M + H) 537. HPLC: 3.33 min. 1H NMR (400MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.75 (m, 1H), 9.89 (m, 1H),8.35-8.05 (m, 3H), 7.44 (m, 2H), 5.27 (m, 1H), 3.75 (s, 3H), 2.99 (m,2H), 2.5 (m, 6H), 2.0 (m, 5H), 1.50 (s, 3H), 1.30 (m, 3H), 1.0 (m, 2H).Example 144 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {2-[2-(1-isopropyl-3,5- dimethyl-1H-pyrazol- 4-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Method B 2-[2-(1-Isopropyl-3,5- dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H-benzocyclohepten-5- ylamine hydrochloride LC/MS: (M + H) 567. HPLC: 4.3min. 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s,1H), 10.0 (m, 1H), 8.31-8.05 (m, 3H), 7.50 (m, 2H), 5.25 (s, 1H), 4.50(m, 1H), 3.0 (m, 2H), 2.52 (s, 3H), 2.48 (s, 3H), 2.0 (m, 5H), 1.47 (s,16H). Example 145 3-tert-Butoxy- azetidine-1- carboxylic acid {6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 4-{7-bromo-3H- imidazo[4,5-b]pyridin- 2-yl}-5-methyl-1-(propan-2-yl)-1H- pyrazole LCMS: 542 (M + H). ¹H NMR (400 MHz, DMSO-d6)δ 13.16 (s, 1H), 8.24 (d, J = 6.8 Hz, 2H), 8.15 (s, 1H), 8.09 (d, J =8.1 Hz, 1H), 7.46 (d, J = 5.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 6.68(d, J = 8.8 Hz, 1H), 4.86 (s, 1H), 4.69-4.60 (m, 1H), 4.45 (d, J = 7.4Hz, 1H), 4.02 (s, 2H), 3.59 (s, 2H), 2.82 (s, 5H), 1.94 (s, 3H), 1.74(s, 2H), 1.42 (d, J = 6.6 Hz, 6H), 1.12 (s, 9H). Example 1463-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5- carboxylic acid {6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 7-Bromo-2-(1- isopropyl-5-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine LCMS: 537 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ13.18 (s, 1H), 9.67 (d, J = 8.7 Hz, 1H), 8.31-8.21 (m, 2H), 8.16 (s,1H), 8.14-8.10 (m, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 8.2 Hz,1H), 5.25 (s, 1H), 4.64 (p, J = 6.5 Hz, 1H), 2.88 (s, 2H), 2.81 (s, 2H),2.07-1.89 (m, 3H), 1.82 (s, 1H), 1.48 (s, 3H), 1.42 (d, J = 6.5 Hz, 5H),1.18 (q, J = 3.7 Hz, 2H), 0.97 (q, J = 4.0 Hz, 2H). Example 1473-tert-Butoxy- azetidine-1- carboxylic acid (6-{2- [5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 7-Bromo-2-[5-methyl- 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridine LCMS: 584 (M + H). ¹HNMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.27-8.22 (m, 2H), 8.17 (s, 1H),8.08 (dd, J = 8.2, 1.9 Hz, 1H), 7.46 (d, J = 5.3 Hz, 1H), 7.36 (d, J =8.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.90-4.80 (m, 1H), 4.59-4.40 (m,2H), 4.00 (td, J = 12.1, 10.4, 6.2 Hz, 3H), 3.59 (dt, J = 8.7, 4.5 Hz,2H), 3.51 (dd, J = 12.9, 10.8 Hz, 2H), 2.84 (s, 4H), 2.14-2.01 (m, 2H),1.94 (q, J = 5.3 Hz, 2H), 1.84 (d, J = 12.8 Hz, 2H), 1.74 (q, J = 11.4,10.2 Hz, 2H), 1.12 (s, 7H), 1.08-1.01 (m, 1H). Example 148 3-(1-Methyl-cyclopropyl)- [1,2,4]oxadiazole-5- carboxylic acid (6-{2- [5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 7-Bromo-2-[5-methyl- 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridine LCMS: 579 (M + H). ¹HNMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.67 (d, J = 8.7 Hz, 1H), 8.28(d, J = 1.9 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 8.10 (dd, J= 8.1, 1.9 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H),5.24 (t, J = 7.0 Hz, 1H), 4.52 (td, J = 11.1, 5.4 Hz, 1H), 4.08-3.93 (m,2H), 3.51 (dd, J = 12.8, 10.7 Hz, 2H), 2.84 (s, 4H), 2.15-1.89 (m, 5H),1.84 (d, J = 12.7 Hz, 3H), 1.48 (s, 3H), 1.21-1.13 (m, 2H), 1.01-0.91(m, 2H). Example 149 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid{6-[2- (1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 4-{7-bromo-3H- imidazo[4,5-b]pyridin- 2-yl}-5-methyl-1-(propan-2-yl)-1H- pyrazole LCMS: 539 (M + H). ¹H NMR (400 MHz, DMSO-d6)δ 13.18 (s, 1H), 9.31 (d, J = 8.8 Hz, 1H), 8.28 (s, 1H), 8.25 (d, J =5.2 Hz, 1H), 8.16 (s, 1H), 8.12 (dd, J = 8.1, 1.9 Hz, 1H), 7.48 (d, J =5.2 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 5.29 (d, J = 5.7 Hz, 1H), 4.64(p, J = 6.6 Hz, 1H), 2.88 (s, 2H), 2.81 (s, 3H), 2.07-1.89 (m, 3H), 1.83(s, 1H), 1.42 (d, J = 6.9 Hz, 15H). Example 150 5-tert-Butyl-[1,2,4]oxadiazole-3- carboxylic acid (6-{2- [5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 7-Bromo-2-[5-methyl- 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridine LCMS: 581 (M + H). ¹HNMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.30 (d, J = 8.9 Hz, 1H), 8.28(t, J = 1.8 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 8.11 (dd, J= 8.3, 1.9 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H),5.28 (d, J = 4.6 Hz, 1H), 4.53 (td, J = 11.4, 5.7 Hz, 1H), 4.07-3.93 (m,3H), 3.51 (dd, J = 12.9, 10.7 Hz, 2H), 2.84 (s, 4H), 2.07 (qd, J = 11.9,11.5, 4.2 Hz, 4H), 1.88-1.76 (m, 3H), 1.42 (s, 8H), 1.16 (q, J = 7.3 Hz,1H). Example 151 5-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-3-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridin-7-yl}-1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 7-Bromo-2-[5-methyl- 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridine LCMS: 579 (M + H). ¹HNMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.25 (d, J = 8.8 Hz, 1H), 8.27(s, 2H), 8.17 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.33 (d,J = 8.5 Hz, 1H), 5.27 (s, 1H), 4.53 (s, 1H), 3.99 (d, J = 11.7 Hz, 2H),3.50 (d, J = 12.6 Hz, 2H), 3.30 (s, 3H, overlaps with H2O peak), 2.85(s, 4H), 2.15-1.73 (m, 7H), 1.54 (s, 2H), 1.38 (s, 2H), 1.16 (s, 2H).Example 152 3-tert-Butoxy- azetidine-1- carboxylic acid {(S)-6-[2-(1-methyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-7-yl]-1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Chiral separation 3-tert-Butoxy- azetidine-1-carboxylic acid{6-[2-(1-isopropyl- 5-methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amide LCMS: 542(M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.24 (d, J = 6.8 Hz,2H), 8.15 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 5.3 Hz, 1H),7.36 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.86 (s, 1H),4.69-4.60 (m, 1H), 4.45 (d, J = 7.4 Hz, 1H), 4.02 (s, 2H), 3.59 (s, 2H),2.82 (s, 5H), 1.94 (s, 3H), 1.74 (s, 2H), 1.42 (d, J = 6.6 Hz, 6H), 1.12(s, 9H). Example 153 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylic acid{(R)- 2-[2-(1,5-dimethyl- 1H-pyrazol-3-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Chiral separation 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylic acid{2-[2- (1,5-dimethyl-1H- pyrazol-3-yl)-3H- imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5- yl}-amide LC/MS: (M +H) 525. HPLC: 3.65 min. 1H NMR (400 MHz, DMSO-d6) δ 13.40 (brs, 1H),10.0 (s, 1H), 8.24-8.05 (m, 3H), 7.50 (m, 2H), 6.75 (s, 1H), 5.26 (m,1H), 3.85 (s, 3H), 3.0 (m, 2H), 2.29 (s, 3H), 2.0 (m, 5H), 1.46 (m,10H). Example 154 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid ((R)- 6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridin-7-yl}-1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4-tetrahydro-naphthalen- 1-yl)-amide LCMS: 579 (M + H). ¹H NMR (400 MHz,DMSO-d6) δ 13.20 (s, 1H), 9.67 (d, J = 8.7 Hz, 1H), 8.28 (d, J = 1.9 Hz,1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 8.10 (dd, J = 8.1, 1.9 Hz,1H), 7.47 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 5.24 (t, J =7.0 Hz, 1H), 4.52 (td, J = 11.1, 5.4 Hz, 1H), 4.08-3.93 (m, 2H), 3.51(dd, J = 12.8, 10.7 Hz, 2H), 2.84 (s, 4H), 2.15-1.89 (m, 5H), 1.84 (d, J= 12.7 Hz, 3H), 1.48 (s, 3H), 1.21-1.13 (m, 2H), 1.01-0.91 (m, 2H).Example 155 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5- carboxylicacid ((S)- 6-{2-[5-methyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}-4-yl]- 3H-imidazo[4,5-1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-b]pyridin- 7-yl}-1,2,3,4- tetrahydro-naphthalen- 1-yl)-amideLCMS: 579 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.67 (d, J= 8.7 Hz, 1H), 8.28 (d, J = 1.9 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17(s, 1H), 8.10 (dd, J = 8.1, 1.9 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.35(d, J = 8.2 Hz, 1H), 5.24 (t, J = 7.0 Hz, 1H), 4.52 (td, J = 11.1, 5.4Hz, 1H), 4.08-3.93 (m, 2H), 3.51 (dd, J = 12.8, 10.7 Hz, 2H), 2.84 (s,4H), 2.15-1.89 (m, 5H), 1.84 (d, J = 12.7 Hz, 3H), 1.48 (s, 3H),1.21-1.13 (m, 2H), 1.01-0.91 (m, 2H). Example 156 5-tert-Butyl-[1,2,4]oxadiazole-3- carboxylic acid ((R)- 6-{2-[5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid(6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4- tetrahydro-naphthalen- 1-yl)-amideLCMS: 581 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.30 (d, J= 8.9 Hz, 1H), 8.28 (t, J = 1.8 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17(s, 1H), 8.11 (dd, J = 8.3, 1.9 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.34(d, J = 8.2 Hz, 1H), 5.28 (d, J = 4.6 Hz, 1H), 4.53 (td, J = 11.4, 5.7Hz, 1H), 4.07-3.93 (m, 3H), 3.51 (dd, J = 12.9, 10.7 Hz, 2H), 2.84 (s,4H), 2.07 (qd, J = 11.9, 11.5, 4.2 Hz, 4H), 1.88-1.76 (m, 3H), 1.42 (s,8H), 1.16 (q, J = 7.3 Hz, 1H). Example 157 5-tert-Butyl-[1,2,4]oxadiazole-3- carboxylic acid ((S)- 6-{2-[5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid(6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4- tetrahydro-naphthalen- 1-yl)-amideLCMS: 581 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.30 (d, J= 8.9 Hz, 1H), 8.28 (t, J = 1.8 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17(s, 1H), 8.11 (dd, J = 8.3, 1.9 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.34(d, J = 8.2 Hz, 1H), 5.28 (d, J = 4.6 Hz, 1H), 4.53 (td, J = 11.4, 5.7Hz, 1H), 4.07-3.93 (m, 3H), 3.51 (dd, J = 12.9, 10.7 Hz, 2H), 2.84 (s,4H), 2.07 (qd, J = 11.9, 11.5, 4.2 Hz, 4H), 1.88-1.76 (m, 3H), 1.42 (s,8H), 1.16 (q, J = 7.3 Hz, 1H). Example 158 3-tert-Butoxy- azetidine-1-carboxylic acid ((R)- 6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- tetrahydro- naphthalen-1-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 3-tert-Butoxy- azetidine-1-carboxylic acid(6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4- tetrahydro-naphthalen- 1-yl)-amideLCMS: 584 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.27-8.22(m, 2H), 8.17 (s, 1H), 8.08 (dd, J = 8.2, 1.9 Hz, 1H), 7.46 (d, J = 5.3Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.90-4.80(m, 1H), 4.59-4.40 (m, 2H), 4.00 (td, J = 12.1, 10.4, 6.2 Hz, 3H), 3.59(dt, J = 8.7, 4.5 Hz, 2H), 3.51 (dd, J = 12.9, 10.8 Hz, 2H), 2.84 (s,4H), 2.14-2.01 (m, 2H), 1.94 (q, J = 5.3 Hz, 2H), 1.84 (d, J = 12.8 Hz,2H), 1.74 (q, J = 11.4, 10.2 Hz, 2H), 1.12 (s, 7H), 1.08-1.01 (m, 1H).Example 159 3-tert-Butoxy- azetidine-1- carboxylic acid ((S)-6-{2-[5-methyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)-amide

Chiral separation 3-tert-Butoxy- azetidine-1-carboxylic acid(6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4- tetrahydro-naphthalen- 1-yl)-amideLCMS: 584 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.27-8.22(m, 2H), 8.17 (s, 1H), 8.08 (dd, J = 8.2, 1.9 Hz, 1H), 7.46 (d, J = 5.3Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.90-4.80(m, 1H), 4.59-4.40 (m, 2H), 4.00 (td, J = 12.1, 10.4, 6.2 Hz, 3H), 3.59(dt, J = 8.7, 4.5 Hz, 2H), 3.51 (dd, J = 12.9, 10.8 Hz, 2H), 2.84 (s,4H), 2.14-2.01 (m, 2H), 1.94 (q, J = 5.3 Hz, 2H), 1.84 (d, J = 12.8 Hz,2H), 1.74 (q, J = 11.4, 10.2 Hz, 2H), 1.12 (s, 7H), 1.08-1.01 (m, 1H).Example 160 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {(R)-2-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Chiral separation 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{2-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-yl}-amide LC/MS: (M + H) 553. HPLC: 4.35 min. 1H NMR (400 MHz, DMSO-d6)δ 13.10 (br.s, 1H), 10.01 (m, 1H), 8.0-8.4 (m, 4H), 7.50 (m, 2H), 5.31(m, 1H), 4.55 (m, 1H), 3.0 (m, 2H), 2.77 (s, 3H), 2.0 (m, 5H), 3H), 1.48(m, 16H) Example 161 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{(R)- 2-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Chiral separation 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{2-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-yl}-amide LC/MS: (M + H) 553. HPLC: 4.35 min. 1H NMR (400 MHz, DMSO-d6)δ 13.10 (br.s, 1H), 10.01 (m, 1H), 8.0-8.4 (m, 4H), 7.50 (m, 2H), 5.31(m, 1H), 4.55 (m, 1H), 3.0 (m, 2H), 2.77 (s, 3H), 2.0 (m, 5H), 3H), 1.48(m, 16H) Example 162 5-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-3-carboxylic acid ((R)- 6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridin-7-yl}-1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 5-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-3-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4-tetrahydro-naphthalen- 1-yl)-amide LCMS: 579 (M + H). ¹H NMR (400 MHz,DMSO-d6) δ 13.21 (s, 1H), 9.25 (d, J = 8.8 Hz, 1H), 8.27 (s, 2H), 8.17(s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.33 (d, J = 8.5 Hz,1H), 5.27 (s, 1H), 4.53 (s, 1H), 3.99 (d, J = 11.7 Hz, 2H), 3.50 (d, J =12.6 Hz, 2H), 3.30 (s, 3H, overlaps with H2O peak), 2.85 (s, 4H),2.15-1.73 (m, 7H), 1.54 (s, 2H), 1.38 (s, 2H), 1.16 (s, 2H). Example 1635-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-3- carboxylic acid ((S)-6-{2-[5-methyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)-amide

Chiral separation 5-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-3-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4-tetrahydro-naphthalen- 1-yl)-amide LCMS: 579 (M + H). ¹H NMR (400 MHz,DMSO-d6) δ 13.21 (s, 1H), 9.25 (d, J = 8.8 Hz, 1H), 8.27 (s, 2H), 8.17(s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.33 (d, J = 8.5 Hz,1H), 5.27 (s, 1H), 4.53 (s, 1H), 3.99 (d, J = 11.7 Hz, 2H), 3.50 (d, J =12.6 Hz, 2H), 3.30 (s, 3H, overlaps with H2O peak), 2.85 (s, 4H),2.15-1.73 (m, 7H), 1.54 (s, 2H), 1.38 (s, 2H), 1.16 (s, 2H). Example 1645-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid {(R)-6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Chiral separation 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid{6-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amideLCMS: 539 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.31 (d, J= 8.8 Hz, 1H), 8.28 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H),8.12 (dd, J = 8.1, 1.9 Hz, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.34 (d, J =8.2 Hz, 1H), 5.29 (d, J = 5.7 Hz, 1H), 4.64 (p, J = 6.6 Hz, 1H), 2.88(s, 2H), 2.81 (s, 3H), 2.07-1.89 (m, 3H), 1.83 (s, 1H), 1.42 (d, J = 6.9Hz, 15H). Example 165 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid{(S)- 6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Chiral separation 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid{6-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amideLCMS: 539 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.31 (d, J= 8.8 Hz, 1H), 8.28 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H),8.12 (dd, J = 8.1, 1.9 Hz, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.34 (d, J =8.2 Hz, 1H), 5.29 (d, J = 5.7 Hz, 1H), 4.64 (p, J = 6.6 Hz, 1H), 2.88(s, 2H), 2.81 (s, 3H), 2.07-1.89 (m, 3H), 1.83 (s, 1H), 1.42 (d, J = 6.9Hz, 15H). Example 166 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid {(R)- 6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4-tetrahydro-naphthalen-1-yl}- amide

Chiral separation 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid {6-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amideLCMS: 537 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.67 (d, J= 8.7 Hz, 1H), 8.31-8.21 (m, 2H), 8.16 (s, 1H), 8.14-8.10 (m, 1H), 7.47(d, J = 5.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 5.25 (s, 1H), 4.64 (p, J= 6.5 Hz, 1H), 2.88 (s, 2H), 2.81 (s, 2H), 2.07-1.89 (m, 3H), 1.82 (s,1H), 1.48 (s, 3H), 1.42 (d, J = 6.5 Hz, 5H), 1.18 (q, J = 3.7 Hz, 2H),0.97 (q, J = 4.0 Hz, 2H). Example 167 3-(1-Methyl- cyclopropyl)-[1,2,4]oxadiazole-5- carboxylic acid {(S)- 6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5- b]pyridin-7-yl]-1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Chiral separation 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid {6-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amideLCMS: 537 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.67 (d, J= 8.7 Hz, 1H), 8.31-8.21 (m, 2H), 8.16 (s, 1H), 8.14-8.10 (m, 1H), 7.47(d, J = 5.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 5.25 (s, 1H), 4.64 (p, J= 6.5 Hz, 1H), 2.88 (s, 2H), 2.81 (s, 2H), 2.07-1.89 (m, 3H), 1.82 (s,1H), 1.48 (s, 3H), 1.42 (d, J = 6.5 Hz, 5H), 1.18 (q, J = 3.7 Hz, 2H),0.97 (q, J = 4.0 Hz, 2H). Example 168 3-tert-Butoxy- azetidine-1-carboxylic acid {6-[2- (1-isopropyl-5- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4-tetrahydro-naphthalen-1-yl}- amide

Method C 4-{7-bromo-3H- imidazo[4,5-b]pyridin- 2-yl}-5-methyl-1-(propan-2-yl)-1H- pyrazole LCMS: 542 (M + H). ¹H NMR (400 MHz, DMSO-d6)δ 13.16 (s, 1H), 8.24 (d, J = 6.8 Hz, 2H), 8.15 (s, 1H), 8.09 (d, J =8.1 Hz, 1H), 7.46 (d, J = 5.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 6.68(d, J = 8.8 Hz, 1H), 4.86 (s, 1H), 4.69-4.60 (m, 1H), 4.45 (d, J = 7.4Hz, 1H), 4.02 (s, 2H), 3.59 (s, 2H), 2.82 (s, 5H), 1.94 (s, 3H), 1.74(s, 2H), 1.42 (d, J = 6.6 Hz, 6H), 1.12 (s, 9H). Example 1693-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5- carboxylic acid {6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 7-Bromo-2-(1- isopropyl-5-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine LCMS: 537 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ13.18 (s, 1H), 9.67 (d, J = 8.7 Hz, 1H), 8.31-8.21 (m, 2H), 8.16 (s,1H), 8.14-8.10 (m, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 8.2 Hz,1H), 5.25 (s, 1H), 4.64 (p, J = 6.5 Hz, 1H), 2.88 (s, 2H), 2.81 (s, 2H),2.07-1.89 (m, 3H), 1.82 (s, 1H), 1.48 (s, 3H), 1.42 (d, J = 6.5 Hz, 5H),1.18 (q, J = 3.7 Hz, 2H), 0.97 (q, J = 4.0 Hz, 2H). Example 1703-tert-Butoxy- azetidine-1- carboxylic acid (6-{2- [5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 7-Bromo-2-[5-methyl- 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridine LCMS: 584 (M + H). ¹HNMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.27-8.22 (m, 2H), 8.17 (s, 1H),8.08 (dd, J = 8.2, 1.9 Hz, 1H), 7.46 (d, J = 5.3 Hz, 1H), 7.36 (d, J =8.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.90-4.80 (m, 1H), 4.59-4.40 (m,2H), 4.00 (td, J = 12.1, 10.4, 6.2 Hz, 3H), 3.59 (dt, J = 8.7, 4.5 Hz,2H), 3.51 (dd, J = 12.9, 10.8 Hz, 2H), 2.84 (s, 4H), 2.14-2.01 (m, 2H),1.94 (q, J = 5.3 Hz, 2H), 1.84 (d, J = 12.8 Hz, 2H), 1.74 (q, J = 11.4,10.2 Hz, 2H), 1.12 (s, 7H), 1.08-1.01 (m, 1H). Example 171 3-(1-Methyl-cyclopropyl)- [1,2,4]oxadiazole-5- carboxylic acid (6-{2- [5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 7-Bromo-2-[5-methyl- 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridine LCMS: 579 (M + H). ¹HNMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.67 (d, J = 8.7 Hz, 1H), 8.28(d, J = 1.9 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 8.10 (dd, J= 8.1, 1.9 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H),5.24 (t, J = 7.0 Hz, 1H), 4.52 (td, J = 11.1, 5.4 Hz, 1H), 4.08-3.93 (m,2H), 3.51 (dd, J = 2.8, 10.7 Hz, 2H), 2.84 (s, 4H), 2.15-1.89 (m, 5H),1.84 (d, J = 12.7 Hz, 3H), 1.48 (s, 3H), 1.21-1.13 (m, 2H), 1.01-0.91(m, 2H). Example 172 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid{6-[2- (1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Method C 4-{7-bromo-3H- imidazo[4,5-b]pyridin- 2-yl}-5-methyl-1-(propan-2-yl)-1H- pyrazole LCMS: 539 (M + H). ¹H NMR (400 MHz, DMSO-d6)δ 13.18 (s, 1H), 9.31 (d, J = 8.8 Hz, 1H), 8.28 (s, 1H), 8.25 (d, J =5.2 Hz, 1H), 8.16 (s, 1H), 8.12 (dd, J = 8.1, 1.9 Hz, 1H), 7.48 (d, J =5.2 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 5.29 (d, J = 5.7 Hz, 1H), 4.64(p, J = 6.6 Hz, 1H), 2.88 (s, 2H), 2.81 (s, 3H), 2.07-1.89 (m, 3H), 1.83(s, 1H), 1.42 (d, J = 6.9 Hz, 15H). Example 173 5-tert-Butyl-[1,2,4]oxadiazole-3- carboxylic acid (6-{2- [5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 7-Bromo-2-[5-methyl- 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridine LCMS: 581 (M + H). ¹HNMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.30 (d, J = 8.9 Hz, 1H), 8.28(t, J = 1.8 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 8.11 (dd, J= 8.3, 1.9 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H),5.28 (d, J = 4.6 Hz, 1H), 4.53 (td, J = 11.4, 5.7 Hz, 1H), 4.07-3.93 (m,3H), 3.51 (dd, J = 12.9, 10.7 Hz, 2H), 2.84 (s, 4H), 2.07 (qd, J = 11.9,11.5, 4.2 Hz, 4H), 1.88-1.76 (m, 3H), 1.42 (s, 8H), 1.16 (q, J = 7.3 Hz,1H). Example 174 5-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-3-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridin-7-yl}-1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Method C 7-Bromo-2-[5-methyl- 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridine LCMS: 579 (M + H). ¹HNMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.25 (d, J = 8.8 Hz, 1H), 8.27(s, 2H), 8.17 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.33 (d,J = 8.5 Hz, 1H), 5.27 (s, 1H), 4.53 (s, 1H), 3.99 (d, J = 11.7 Hz, 2H),3.50 (d, J = 12.6 Hz, 2H), 3.30 (s, 3H, overlaps with H2O peak), 2.85(s, 4H), 2.15-1.73 (m, 7H), 1.54 (s, 2H), 1.38 (s, 2H), 1.16 (s, 2H).Example 175 3-tert-Butoxy- azetidine-1- carboxylic acid {(S)-6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Chiral separation 3-tert-Butoxy- azetidine-1-carboxylic acid{6-[2-(1-isopropyl- 5-methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amide LCMS: 542(M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.24 (d, J = 6.8 Hz,2H), 8.15 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 5.3 Hz, 1H),7.36 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.86 (s, 1H),4.69-4.60 (m, 1H), 4.45 (d, J = 7.4 Hz, 1H), 4.02 (s, 2H), 3.59 (s, 2H),2.82 (s, 5H), 1.94 (s, 3H), 1.74 (s, 2H), 1.42 (d, J = 6.6 Hz, 6H), 1.12(s, 9H). Example 176 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylic acid{(R)- 2-[2-(1,5-dimethyl- 1H-pyrazol-3-yl)-3H- imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Chiral separation 5-tert-Butyl- [1,3,4]oxadiazole-2- carboxylic acid{2-[2- (1,5-dimethyl-1H- pyrazol-3-yl)-3H- imidazo[4,5-b]pyridin-7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5- yl}-amide LC/MS: (M +H) 525. HPLC: 3.65 min. 1H NMR (400 MHz, DMSO-d6) δ 13.40 (brs, 1H),10.0 (s, 1H), 8.24-8.05 (m, 3H), 7.50 (m, 2H), 6.75 (s, 1H), 5.26 (m,1H), 3.85 (s, 3H), 3.0 (m, 2H), 2.29 (s, 3H), 2.0 (m, 5H), 1.46 (m,10H). Example 177 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid ((R)- 6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridin-7-yl}-1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4-tetrahydro-naphthalen- 1-yl)-amide LCMS: 579 (M + H). ¹H NMR (400 MHz,DMSO-d6) δ 13.20 (s, 1H), 9.67 (d, J = 8.7 Hz, 1H), 8.28 (d, J = 1.9 Hz,1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 8.10 (dd, J = 8.1, 1.9 Hz,1H), 7.47 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 5.24 (t, J =7.0 Hz, 1H), 4.52 (td, J = 11.1, 5.4 Hz, 1H), 4.08-3.93 (m, 2H), 3.51(dd, J = 12.8, 10.7 Hz, 2H), 2.84 (s, 4H), 2.15-1.89 (m, 5H), 1.84 (d, J= 12.7 Hz, 3H), 1.48 (s, 3H), 1.21-1.13 (m, 2H), 1.01-0.91 (m, 2H).Example 178 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5- carboxylicacid ((S)- 6-{2-[5-methyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)-amide

Chiral separation 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4-tetrahydro-naphthalen- 1-yl)-amide LCMS: 579 (M + H). ¹H NMR (400 MHz,DMSO-d6) δ 13.20 (s, 1H), 9.67 (d, J = 8.7 Hz, 1H), 8.28 (d, J = 1.9 Hz,1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 8.10 (dd, J = 8.1, 1.9 Hz,1H), 7.47 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 5.24 (t, J =7.0 Hz, 1H), 4.52 (td, J = 11.1, 5.4 Hz, 1H), 4.08-3.93 (m, 2H), 3.51(dd, J = 12.8, 10.7 Hz, 2H), 2.84 (s, 4H), 2.15-1.89 (m, 5H), 1.84 (d, J= 12.7 Hz, 3H), 1.48 (s, 3H), 1.21-1.13 (m, 2H), 1.01-0.91 (m, 2H).Example 179 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid ((R)-6-{2-[5-methyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)-amide

Chiral separation 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid(6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4- tetrahydro-naphthalen- 1-yl)-amideLCMS: 581 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.30 (d, J= 8.9 Hz, 1H), 8.28 (t, J = 1.8 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17(s, 1H), 8.11 (dd, J = 8.3, 1.9 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.34(d, J = 8.2 Hz, 1H), 5.28 (d, J = 4.6 Hz, 1H), 4.53 (td, J = 11.4, 5.7Hz, 1H), 4.07-3.93 (m, 3H), 3.51 (dd, J = 12.9, 10.7 Hz, 2H), 2.84 (s,4H), 2.07 (qd, J = 11.9, 11.5, 4.2 Hz, 4H), 1.88-1.76 (m, 3H), 1.42 (s,8H), 1.16 (q, J = 7.3 Hz, 1H). Example 180 5-tert-Butyl-[1,2,4]oxadiazole-3- carboxylic acid ((S)- 6-{2-[5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid(6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4- tetrahydro-naphthalen- 1-yl)-amideLCMS: 581 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.30 (d, J= 8.9 Hz, 1H), 8.28 (t, J = 1.8 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.17(s, 1H), 8.11 (dd, J = 8.3, 1.9 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.34(d, J = 8.2 Hz, 1H), 5.28 (d, J = 4.6 Hz, 1H), 4.53 (td, J = 11.4, 5.7Hz, 1H), 4.07-3.93 (m, 3H), 3.51 (dd, J = 12.9, 10.7 Hz, 2H), 2.84 (s,4H), 2.07 (qd, J = 11.9, 11.5, 4.2 Hz, 4H), 1.88-1.76 (m, 3H), 1.42 (s,8H), 1.16 (q, J = 7.3 Hz, 1H). Example 181 3-tert-Butoxy- azetidine-1-carboxylic acid ((R)- 6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5- b]pyridin-7-yl}-1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 3-tert-Butoxy- azetidine-1-carboxylic acid(6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4- tetrahydro-naphthalen- 1-yl)-amideLCMS: 584 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.27-8.22(m, 2H), 8.17 (s, 1H), 8.08 (dd, J = 8.2, 1.9 Hz, 1H), 7.46 (d, J = 5.3Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.90-4.80(m, 1H), 4.59-4.40 (m, 2H), 4.00 (td, J = 12.1, 10.4, 6.2 Hz, 3H), 3.59(dt, J = 8.7, 4.5 Hz, 2H), 3.51 (dd, J = 12.9, 10.8 Hz, 2H), 2.84 (s,4H), 2.14-2.01 (m, 2H), 1.94 (q, J = 5.3 Hz, 2H), 1.84 (d, J = 12.8 Hz,2H), 1.74 (q, J = 11.4, 10.2 Hz, 2H), 1.12 (s, 7H), 1.08-1.01 (m, 1H).Example 182 3-tert-Butoxy- azetidine-1- carboxylic acid ((S)-6-{2-[5-methyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)-amide

Chiral separation 3-tert-Butoxy- azetidine-1-carboxylic acid(6-{2-[5-methyl-1- (tetrahydro-pyran-4-yl)- 1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4- tetrahydro-naphthalen- 1-yl)-amideLCMS: 584 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.27-8.22(m, 2H), 8.17 (s, 1H), 8.08 (dd, J = 8.2, 1.9 Hz, 1H), 7.46 (d, J = 5.3Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.90-4.80(m, 1H), 4.59-4.40 (m, 2H), 4.00 (td, J = 12.1, 10.4, 6.2 Hz, 3H), 3.59(dt, J = 8.7, 4.5 Hz, 2H), 3.51 (dd, J = 12.9, 10.8 Hz, 2H), 2.84 (s,4H), 2.14-2.01 (m, 2H), 1.94 (q, J = 5.3 Hz, 2H), 1.84 (d, J = 12.8 Hz,2H), 1.74 (q, J = 11.4, 10.2 Hz, 2H), 1.12 (s, 7H), 1.08-1.01 (m, 1H).Example 183 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid {(R)-2-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Chiral separation 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{2-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-yl}-amide LC/MS: (M + H) 553. HPLC: 4.35 min. ¹H NMR (400 MHz, DMSO-d6)δ 13.10 (br.s, 1H), 10.01 (m, 1H), 8.0-8.4 (m, 4H), 7.50 (m, 2H), 5.31(m, 1H), 4.55 (m, 1H), 3.0 (m, 2H), 2.77 (s, 3H), 2.0 (m, 5H), 3H), 1.48(m, 16H) Example 184 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{(S)- 2-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 6,7,8,9-tetrahydro- 5H- benzocyclohepten-5- yl}-amide

Chiral separation 3-tert-Butyl- [1,2,4]oxadiazole-5- carboxylic acid{2-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-6,7,8,9- tetrahydro-5H-benzocyclohepten-yl}- amide LC/MS: (M + H) 553. HPLC: 4.35 min. 1H NMR(400 MHz, DMSO-d6) δ 13.10 (br.s, 1H), 10.01 (m, 1H), 8.0-8.4 (m, 4H),7.50 (m, 2H), 5.31 (m, 1H), 4.55 (m, 1H), 3.0 (m, 2H), 2.77 (s, 3H), 2.0(m, 5H), 3H), 1.48 (m, 16H) Example 185 5-(1-Methyl- cyclopropyl)-[1,2,4]oxadiazole-3- carboxylic acid ((R)- 6-{2-[5-methyl-1-(tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]- 3H-imidazo[4,5-b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)- amide

Chiral separation 5-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-3-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4-tetrahydro-naphthalen- 1-yl)-amide LCMS: 579 (M + H). ¹H NMR (400 MHz,DMSO-d6) δ 13.21 (s, 1H), 9.25 (d, J = 8.8 Hz, 1H), 8.27 (s, 2H), 8.17(s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.33 (d, J = 8.5 Hz,1H), 5.27 (s, 1H), 4.53 (s, 1H), 3.99 (d, J = 11.7 Hz, 2H), 3.50 (d, J =12.6 Hz, 2H), 3.30 (s, 3H, overlaps with H2O peak), 2.85 (s, 4H),2.15-1.73 (m, 7H), 1.54 (s, 2H), 1.38 (s, 2H), 1.16 (s, 2H). Example 1865-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-3- carboxylic acid ((S)-6-{2-[5-methyl-1- (tetrahydro-pyran-4- yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5- b]pyridin-7-yl}- 1,2,3,4-tetrahydro- naphthalen-1-yl)-amide

Chiral separation 5-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-3-carboxylic acid (6-{2- [5-methyl-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H- imidazo[4,5-b]pyridin- 7-yl}-1,2,3,4-tetrahydro-naphthalen- 1-yl)-amide LCMS: 579 (M + H). ¹H NMR (400 MHz,DMSO-d6) δ 13.21 (s, 1H), 9.25 (d, J = 8.8 Hz, 1H), 8.27 (s, 2H), 8.17(s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.33 (d, J = 8.5 Hz,1H), 5.27 (s, 1H), 4.53 (s, 1H), 3.99 (d, J = 11.7 Hz, 2H), 3.50 (d, J =12.6 Hz, 2H), 3.30 (s, 3H, overlaps with H2O peak), 2.85 (s, 4H),2.15-1.73 (m, 7H), 1.54 (s, 2H), 1.38 (s, 2H), 1.16 (s, 2H). Example 1875-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid {(R)-6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Chiral separation 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid{6-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amideLCMS: 539 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.31 (d, J= 8.8 Hz, 1H), 8.28 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H),8.12 (dd, J = 8.1, 1.9 Hz, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.34 (d, J =8.2 Hz, 1H), 5.29 (d, J = 5.7 Hz, 1H), 4.64 (p, J = 6.6 Hz, 1H), 2.88(s, 2H), 2.81 (s, 3H), 2.07-1.89 (m, 3H), 1.83 (s, 1H), 1.42 (d, J = 6.9Hz, 15H). Example 188 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid{(S)- 6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-7-yl]- 1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Chiral separation 5-tert-Butyl- [1,2,4]oxadiazole-3- carboxylic acid{6-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amideLCMS: 539 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.31 (d, J= 8.8 Hz, 1H), 8.28 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H),8.12 (dd, J = 8.1, 1.9 Hz, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.34 (d, J =8.2 Hz, 1H), 5.29 (d, J = 5.7 Hz, 1H), 4.64 (p, J = 6.6 Hz, 1H), 2.88(s, 2H), 2.81 (s, 3H), 2.07-1.89 (m, 3H), 1.83 (s, 1H), 1.42 (d, J = 6.9Hz, 15H). Example 189 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid {(R)- 6-[2-(1-isopropyl-5- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-7-yl]- 1,2,3,4-tetrahydro-naphthalen-1-yl}- amide

Chiral separation 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid {6-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amideLCMS: 537 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.67 (d, J= 8.7 Hz, 1H), 8.31-8.21 (m, 2H), 8.16 (s, 1H), 8.14-8.10 (m, 1H), 7.47(d, J = 5.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 5.25 (s, 1H), 4.64 (p, J= 6.5 Hz, 1H), 2.88 (s, 2H), 2.81 (s, 2H), 2.07-1.89 (m, 3H), 1.82 (s,1H), 1.48 (s, 3H), 1.42 (d, J = 6.5 Hz, 5H), 1.18 (q, J = 3.7 Hz, 2H),0.97 (q, J = 4.0 Hz, 2H). Example 190 3-(1-Methyl- cyclopropyl)-[1,2,4]oxadiazole-5- carboxylic acid {(S)- 6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5- b]pyridin-7-yl]-1,2,3,4-tetrahydro- naphthalen-1-yl}- amide

Chiral separation 3-(1-Methyl- cyclopropyl)- [1,2,4]oxadiazole-5-carboxylic acid {6-[2- (1-isopropyl-5-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 7-yl]-1,2,3,4- tetrahydro-naphthalen- 1-yl}-amideLCMS: 537 (M + H). ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.67 (d, J= 8.7 Hz, 1H), 8.31-8.21 (m, 2H), 8.16 (s, 1H), 8.14-8.10 (m, 1H), 7.47(d, J = 5.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 5.25 (s, 1H), 4.64 (p, J= 6.5 Hz, 1H), 2.88 (s, 2H), 2.81 (s, 2H), 2.07-1.89 (m, 3H), 1.82 (s,1H), 1.48 (s, 3H), 1.42 (d, J = 6.5 Hz, 5H), 1.18 (q, J = 3.7 Hz, 2H),0.97 (q, J = 4.0 Hz, 2H).

Assay 1: BTK IC50 Enzyme Assay

The following describes a microfluidic, off-chip mobility shift kinaseassay used to measure inherent potency of compounds against BTK enzyme.Compounds described by embodiments of the present invention were assayedusing this protocol and the data from the same is recorded in Table 2within the column labeled: “Time Dependent BTK Enzyme Assay IC₅₀”. 2.5×stocks of full-length human BTK (08-080) from CarnaBio USA, Inc.,Natick, Mass., 1.6×ATP and appropriate kinKDR peptide substrate(FITC-AHA-EEPLYWSFPAKKK-NH2) were prepared in kinase reaction bufferconsisting of 25 mM MgCl2, 0.015% Brij-35 (30%), 100 mM Hepes, pH 7.5,and 10 mM DTT. 5 uL of enzyme buffer and 7.5 uL of ATP/kinKDR peptidesubstrate mix were added to Matrix (#115304) 384-well, sterile,polypropylene plates (Thermo Fisher Scientific, Hudson, N.H.) with 125nL of serially diluted compounds prepared in 100% DMSO, and incubatedfor 90 min. at 27 C. Following the incubation period, reactions werestopped by adding 60 uL stop buffer consisting of 100 mM Hepes, pH 7.5,0.015% Brij-35 (30%), 0.277% Coating Reagent #3 (Caliper Life Sciences,Mountain View, Calif.), 5% DMSO. Stopped reactions were monitored at −2PSI, −3000 V/−700 V in a LabChip 3000 plate reader from Caliper LifeSciences, a PerkinElmer Company (Hopkinton, Mass.), and the activity wasmeasured by off-chip mobility shift assay measuring the charge/massdifference between substrate and product resulting from peptidephosphorilation. IC50 and efficacy were determined by plotting log[Inhibitor] vs. % Activity in GeneData Screener (Basel, Switzerland).

Assay 2: PBMC IC50 Cell Assay

Btk is critical for mediating the signalling of B cell antigen receptor(BCR) after anti-IgM stimulation. Based on this principle, a functionalcell-based assay was established to determine the potency of compoundsat inhibiting anti-IgM-induced expression of CD69, a downstream BCRsignaling event, in freshly isolated human peripheral blood mononuclearcells (PBMCs). In the assay, a 90 μl PBMC suspension containing 2.5×10⁵cells was pre-treated with 10 μl of test compound at variousconcentrations for an hour, and then incubated overnight (approximately16-18 hours) with 5 μl 420 μg/ml affiniPure F(ab′)₂ fragment goatanti-human IgM Fc fragment per well (Dianova, Cat.No.: 109-006-129).After the incubation, the cells were washed and immunostained with anAPC-labeled mouse anti-human CD69 (BD Biosciences; clone: FN50), aPerCP-Cy5.5 labelled mouse anti-human CD19 (BD Biosciences; clone:SJ25C1) and a FITC-labelled mouse anti-human CD3 (BD Biosciences; clone:HIT3a), and fixed for flow cytometric analysis of CD69 expression onCD19 positive cells (B cells). The percentage of CD69 expressing CD19positive cells was plotted against the concentrations of test compoundsto obtain a concentration response curve, and calculated an IC₅₀ valueas a measure of the potency of test compounds in the assay.

Assay 3: Time Dependent Human Whole Blood IC50 Assay

Compounds described by embodiments of the present invention were assayedusing a human whole blood assay. The data from the same is recordedbelow within the column labeled: “Time Dependent Human Whole Blood BTKEnzyme Assay IC50”.

Example 191. Biological Data

Assay 1: Btk Enzymatic IC50 Assay

Assay 2: Btk PBMC IC50 Assay

Assay 3: Human Whole Blood IC50 Assay

Results are given in the following table.

Assay A Assay B Assay C Example (IC₅₀) (IC₅₀) (IC₅₀) 82 A A — 78 A B B79 A B B 153 A B B 37 A B — 121 A B C 85 A B — 20 A B — 75 A B — 12 A BB 24 A B B 52 A B — 89 A B B 155 A B C 10 A B — 49 A B — 79 A B C 30 A B— 38 A B — 92 A B C 51 A B — 42 A B — 46 A B — 16 A B — 45 A B — 40 A B— 163 A B — 33 A B B 83 A B B 74 A B C 119 A B C 123 A B B 149 A B C 8 AB — 160 A B B 54 A B — 61 A B — 86 A B C 41 A B — 115 A B B 23 A B — 39A A — 21 A B — 32 A B — 84 A B — 11 A B C 43 A B — 56 A B B 97 A — — 124A C C 131 A B C 143 A B C 1 A B C 3 A B B 27 A B — 127 A C — 142 A B B72 A B C 91 A B B 63 A B — 109 A A — 107 A C C 165 A B C 14 A C — 119 AB — 87 A B — 59 A B — 106 A B — 151 A B — 167 A C B 2 A B B 108 A C C110 A B — 157 A B B 6 A B — 29 A B — 150 A B B 133 A B B 137 A C B 120 AB B 118 A B B 148 A C C 69 A B — 58 A B — 100 A B — 96 A B B 135 A B B67 A C — 114 A B C 105 A B — 162 A B — 35 A B — 134 A B B 140 A C D 19 AB — 144 A B C 115 A B D 136 A B C 145 A C — 117 A B — 147 A B — 156 A B— 139 B B — 138 B B D 125 B B D 100 B B — 113 B B C 146 B B — 101 B B —126 B B — 111 B B D 116 B B C 26 B B C 102 B C — 124 B B C 164 B B D 95B B — 73 B B — 98 B — — 154 B C — 158 B B — 132 B B B 112 B C — 70 B B C152 B B — 17 B C — 166 B C — 68 B C — 47 B C — 104 B C — 44 B C — 22 B C— 62 B C — 159 B D — 81 B C C 31 B C — 25 B C — 34 B D — 71 B C — 90 B C— 77 B C — 53 B C — 64 B C — 122 B D — 60 B C — 93 B — — 13 B C — 36 B D— 80 B D — 57 B D — 48 B D — 55 B C — 88 B D — 15 B D — 50 B D — 161 B D— 141 C D — 9 D — — 18 D D — 28 D D — 99 D — — A: IC50 < 1 nM B: IC50 =1 nM-10 nM C: IC50 = 10 nM-100 nM D: IC50 > 100 nM

Example 192. Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid,sterile filtered, transferred into injection vials, is lyophilized understerile conditions and is sealed under sterile conditions. Eachinjection vial contains 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention is melted with 100 g of soy lecithin and 1400 g ofcocoa butter, is poured into moulds and is allowed to cool. Eachsuppository contains 20 mg of active ingredient.

(C) Solution: A solution is prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g ofNa₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbidistilled water. The pH is adjusted to 6.8, and the solution is madeup to 1 l and sterilized by irradiation. This solution could be used inthe form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionis mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate is pressed to give tablets in aconventional manner in such a way that each tablet contains 10 mg ofactive ingredient.

(F) Coated tablets: Tablets are pressed analogously to Example E andsubsequently are coated in a conventional manner with a coating ofsucrose, potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionare introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contains 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bidistilled water is sterile filtered,transferred into ampoules, is lyophilized under sterile conditions andis sealed under sterile conditions. Each ampoule contains 10 mg ofactive ingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention are dissolved in 10 l of isotonic NaCl solution, and thesolution is transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14mg.

While a number of embodiments of this invention are described herein, itis apparent that the basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1. A compound of formula I,

or a tautomer, or a pharmaceutically acceptable salt thereof, wherein: X is C(R)₂ or O; Y is —O—, —S—, —SO₂—, —SO—, —C(O)—, —CO₂—, —C(O)N(R²)—, —NR²C(O)—, —NR²C(O)N(R)—, —NR²SO₂—, or —N(R²)—; R¹ is C₆₋₁₀ aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted; Ring Z is C₆₋₁₀ aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted; each R^(a) is independently —R, halogen, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; or two R^(a) groups, together with the atoms to which each is attached, forms a C₆₋₁₀ aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted; each R is independently hydrogen, C₁₋₆ aliphatic, C₆₋₁₀ aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted; or two R groups on the same atom are taken together with the atom to which they are attached to form a C₆₋₁₀ aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-15 membered fused aryl ring; a 6-15 membered saturated or partially unsaturated fused carbocyclic ring; a 10-15 membered fused heteroaryl ring; or a 6-15 membered saturated or partially unsaturated fused heterocyclic ring; each of which is optionally substituted; n is 0, 1, or 2; and p is 0, 1, 2, or
 3. 2. The compound of claim 1, wherein X is CH₂.
 3. The compound of claim 1, wherein X is O.
 4. The compound of claim 1, wherein Y is —C(O)N(R²)—, —NR²C(O)—, —NR²C(O)N(R)—, or —NR²SO₂.
 5. The compound of claim 1, wherein R¹ is an optionally substituted 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R¹ is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
 6. The compound of claim 5, wherein R¹ is azocinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, piperidine-one, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyridine, tetrahydropyran, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, or azetidinyl; each of which is optionally substituted.
 7. The compound of claim 6, wherein R¹ is selected from:


8. The compound of claim 1, wherein Ring Z is a 3-8 membered saturated or partially unsaturated carbocyclic ring or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted.
 9. The compound of claim 8, wherein Ring Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, or isothiazolyl; each of which is optionally substituted.
 10. The compound of claim 9, wherein Ring Z is


11. The compound of claim 10, wherein Ring Z is


12. The compound of claim 1, of formula II,

or a tautomer, or a pharmaceutically acceptable salt thereof.
 13. The compound of claim 1, of formula III,

or a tautomer, or a pharmaceutically acceptable salt thereof.
 14. The compound of claim 1, of formula IV,

or a tautomer, or a pharmaceutically acceptable salt thereof.
 15. The compound of claim 1, selected from

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim 1, wherein the compound is one of the following compounds: 3-tert-butyl-N-[(5R)-2-{2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide (82), 5-tert-butyl-N-[(5R)-2-{2-[3-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (78), 5-tert-butyl-N-[(5R)-2-{2-[5-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (79), 5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {(R)-2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (153), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (37), 5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (121), 3-tert-butyl-N-{2-[2-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}-1,2,4-oxadiazole-5-carboxamide (85), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (20), 3-tert-butyl-N-[(1R)-6-[2-(1-cyclopropyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5-carboxamide (75), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (12), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (24), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (52), 5-tert-butyl-N-[(5S)-2-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (89), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid ((S)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (155), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(S)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (10), 5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {(S)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (49), 5-tert-butyl-N-[(5R)-2-{2-[5-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (79) 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (30), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (38), 5-tert-butyl-N-[(5R)-2-{2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2-oxazole-3-carboxamide (92), 3-tert-Butoxy-azetidine-1-carboxylic acid {(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (51), 5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (42), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (46), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(S)-8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (16), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(S)-8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (45), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (40), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid ((S)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (163), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (33), 3-tert-butyl-N-{2-[2-(1-cyclopropyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}-1,2,4-oxadiazole-5-carboxamide (83), 3-tert-butyl-N-[(1R)-6-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5-carboxamide (74), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(S)-6-[2-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (119), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (123), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (149), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (8), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (160), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (54), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (61), 5-tert-butyl-N-(2-{2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide (86), 5-(1-Methyl-cyclopropyl)-isoxazole-3-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (41), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid ((S)-6-{2-[3-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (115), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (23), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (39), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (21), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (32), 5-tert-butyl-N-(2-{2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide (84), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (11), 3-tert-Butoxy-azetidine-1-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (43), 5-(1-Methyl-cyclopropyl)-isoxazole-3-carboxylic acid {(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (56), 3-tert-butyl-N-{2-[2-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}-1,2,4-oxadiazole-5-carboxamide (97), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (124), 5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {2-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (131), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (143), 3-tert-butyl-N-[(5R)-2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide (1), 5-tert-butyl-N-[2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (3), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (27), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (127), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (142), 5-tert-butyl-N-[(5R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2-oxazole-3-carboxamide (72), 5-tert-butyl-N-(2-{2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2-oxazole-3-carboxamide (91), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (63), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (109), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {6-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (107), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(S)-6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (165), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (14), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(S)-6-[2-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (119), 5-tert-butyl-N-[(5R)-2-{2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (87), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (59), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (106), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (151), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {(S)-6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (167), N-[(5S)-2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide (2), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {6-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (108), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (110), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid ((S)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (157), 3-tert-butyl-N-[2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide (6), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (29), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (150), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (133), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid ((R)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (137), 5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid (2-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide (120) 5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (118), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (148) 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-amide (69), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (58), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-6-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (100), 3-tert-butyl-N-[(1R)-6-{2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5-carboxamide (96), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (135), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {6-[2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (67), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-6-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (114), 5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {6-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (105), 5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid ((R)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (162), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (35), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (134), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid (6-{2-[3,5-dimethyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (140), 5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {(S)-8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (19), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (144), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid ((S)-6-{2-[3-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (115), 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (136), 3-tert-Butoxy-azetidine-1-carboxylic acid {6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (145), 3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-5-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (117), 3-tert-Butoxy-azetidine-1-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (147), 5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid ((R)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (156)
 17. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
 18. A method for inhibiting BTK, or a mutant thereof, activity in a patient or in a biological sample, comprising the step of administering to said patient or contacting said biological sample with a compound of claim 1, or a physiologically acceptable salt thereof.
 19. A method for treating a BTK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound of claim
 1. 20. The method of claim 19, wherein the disorder is selected from inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosis fungoides, acute inflammatory responses, acute respiratory distress syndrome, ischemia/reperfusion injury, and Graves' disease.
 21. A method for treating lupus in a subject, comprising the step of administering to said subject a compound of claim 1, or a physiologically acceptable salt thereof. 